Infectious Diseases II PDF

Infectious Diseases II
Simon Lam, Pharm.D., FCCM, BCCCP, BCPS
Cleveland Clinic
Cleveland, Ohio
Seth R. Bauer, Pharm.D., FCCM, BCCCP, BCPS

Cleveland Clinic
Cleveland, Ohio
2016 ACCP/SCCM Critical Care Pharmacy Preparatory Review and Recertification Course
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Learning Objectives LOS Length of stay

MALDI-TOF Matrix-assisted laser desorption-
1. Compose a plan to incorporate the metrics of the ionization/time of flight
Surgical Care Improvement Project and the Ameri- MIC Minimum inhibitory concentration
can College of Surgeons National Surgical Quality MRSA Methicillin-resistant Staphylococcus
Improvement Program into pre- and postsurgical aureus
care. MSSA Methicillin-sensitive Staphylococcus
2. Identify key members of an antimicrobial steward- aureus
ship team and common strategies used by the team OI Opportunistic infection
to optimize antibiotic use. PCR Polymerase chain reaction
3. Provide empiric antibiotic therapy recommendations PCT Procalcitonin
for critically ill patients with community-acquired PD Pharmacodynamics
or health care–associated meningitis. PK Pharmacokinetics
4. Differentiate different microbiological rapid diag- PNA FISH Peptide nucleic acid fluorescent in situ
nostic tests and their relative advantages and hybridization
disadvantages. SCIP Surgical Care Improvement Project
5. Devise an antimicrobial management strategy using SOT Solid organ transplantation
a procalcitonin-guided strategy. SSI Surgical site infection
6. Devise a strategy to evaluate antibiotic susceptibil- UTI Urinary tract infection
ity reports that incorporates an understanding of
microbiology method, breakpoint evaluation, and
pharmacokinetic/pharmacodynamic assessment. Self-Assessment Questions
7. Analyze therapeutic options for the treatment of Answers and explanations to these questions may be
multidrug-resistant pathogens in the intensive care found at the end of this chapter.
unit (ICU).
8. Devise an optimal treatment plan for critically 1. A 56-year-old man (weight 140 kg) is scheduled to
ill immunocompromised patients with infectious have elective coronary artery bypass surgery with
diseases. aortic valve bioprosthetic replacement. The patient
9. Distinguish each of the commonly used antifungal has a medical history of diabetes and hypertension.
agents and their place in therapy in an ICU setting. He reports no drug allergies and has a calculated cre-
atinine clearance (CrCl) of 90 mL/minute/1.73 m2.
It is anticipated that the patient will be admitted to
Abbreviations in This Chapter the cardiovascular surgery intensive care unit (ICU)
after the surgery with two chest tubes placed for
ACS NSQIP American College of Surgeons National drainage. Which is the most appropriate antimicro-
Surgical Quality Improvement Program bial prophylactic regimen for the patient?
AST Antimicrobial susceptibility testing A. Cefazolin 2 g x 1 within 2 hours before inci-
CAUTI Catheter-associated urinary tract infection sion and administered every 8 hours until chest
CDC Centers for Disease Control and tubes are removed.
Prevention B. Vancomycin 2 g x 1 within 2 hours before inci-
CLSI Clinical and Laboratory Standards Institute sion and administered every 12 hours until 48
CMS Centers for Medicare & Medicaid Services hours after surgery.
CoNS Coagulase-negative staphylococci C. Cefazolin 3 g x 1 within 1 hour before incision,
CRE Carbapenem-resistant Enterobacteriaceae re-dosed if surgery lasts more than 4 hours, and
ESBL Extended-spectrum β-lactamase continued for 48 hours after surgery.
HAART Highly active antiretroviral therapy D. Cefazolin 2 g x 1, within 1 hour before surgery,
ICU Intensive care unit re-dosed if surgery lasts more than 4 hours, and
KPC Klebsiella pneumoniae carbapenemase continued for 48 hours after surgery.
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2. Which statement best describes antimicrobial stew- A. Change piperacillin/tazobactam to cefepime.

ardship in the ICU? B. Add tobramycin to the current regimen.
A. Formal antimicrobial stewardship team C. Add levofloxacin to the current regimen.
membership should be reserved for clinical D. Change piperacillin/tazobactam to meropenem.
pharmacists with infectious diseases training.
B. The main goal of antimicrobial stewardship 5. An 81-year-old man is admitted to the medical ICU
efforts is to decrease antimicrobial expenditures. with presumed line-associated sepsis. Blood cultures
C. Daily clinical activities of a critical care are obtained that grow pan-sensitive Enterobacter
pharmacist may constitute an antimicrobial cloacae. The patient is being treated with
stewardship effort. intravenous ceftriaxone, and the offending central
D. Antimicrobial stewardship should not be insti- venous catheter is removed. The patient initially
tuted in critically ill patients because restriction responds, but on day 10 of therapy, he becomes
of antimicrobial choices may worsen outcomes. febrile, and blood cultures are re-sent. At that time,
the patient was maintained on ceftriaxone because
3. P.G., a 33-year-old woman with a history of he was hemodynamically stable. Gram stain for the
hydrocephalus since early childhood requiring new blood cultures is positive for lactose-positive
placement of an internal cerebrospinal fluid (CSF) gram-negative bacilli. Which is the most appropriate
shunt, presents with a temperature of 102.8°F action for this patient’s antimicrobial management?
(39.3°C), an altered mental status, and a white blood A. Change ceftriaxone to ceftazidime.
cell count of 19 x 103 cells/mm3. After a computed B. Change ceftriaxone to piperacillin/tazobactam.
tomography (CT) scan reveals no cause for concern C. Change ceftriaxone to meropenem.
about brain shift, a lumbar puncture is performed. D. Continue ceftriaxone alone.
Initial cell count shows elevated CSF white blood
cells with a high proportion of neutrophils and low 6. An 86-year-old woman with a history of end-
glucose. Neurosurgery is consulted for a presumed stage renal disease is admitted to the hospital
CSF shunt infection. Which empiric system with respiratory stress requiring intubation, fluid
antibiotic regimen is most appropriate? resuscitation, and hemodynamic monitoring.
A. Ceftriaxone and ampicillin. Bronchoalveolar lavage cultures show methicillin-
B. Ceftriaxone and vancomycin. resistant Staphylococcus aureus (MRSA). The
C. Piperacillin/tazobactam and tobramycin. patient is being treated with intravenous vancomycin.
D. Cefepime and vancomycin. On day 4 of therapy, the patient develops fever,
leucocytosis, and erythema around the insertion site
4. A 75-year-old man is admitted to the medical ICU of her tunneled dialysis catheter. Blood cultures are
from the emergency department with septic shock. sent, and the dialysis catheter is removed. Gram
He is fluid resuscitated and administered broad- stain from blood cultures is significant for gram-
spectrum antibiotics with piperacillin/tazobactam positive cocci in pairs and chains. The medical
and vancomycin. On day 2 of therapy, the patient team discontinues vancomycin and approaches you
remains hemodynamically unstable, requiring to inquire about treatment options for this patient.
norepinephrine. The patient’s blood culture is Which agent is most appropriate for this patient?
positive, according to the institution’s microbiology A. Daptomycin.
laboratory, which recently implemented rapid B. Linezolid.
diagnostic tests using nanoparticle microarray C. Ceftaroline.
technology, and the microarray results show the D. Tigecycline.
presence of Escherichia coli with the CTX-M
resistance gene. Which intervention regarding the
patient’s antimicrobial therapy is most appropriate?
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7. A 35-year-old man is admitted to the medical ICU A. Continue meropenem, gentamicin, and vanco-
with respiratory distress. He reports a 3-week history mycin for 14 days.
of cough and pleuritic chest pain that has worsened B. Discontinue all empiric antimicrobials and
with time. Chest radiography is performed, which initiate ampicillin intravenously to treat until
shows bilateral infiltrates with ground-glass neutrophils recover.
opacities. The patient is HIV positive and not C. Discontinue vancomycin and continue merope-
currently receiving antiretroviral therapy because of nem and gentamicin until neutrophil recovery.
nonadherence. The patient requires intubation and D. Add voriconazole and continue all other anti-
is receiving 40% fraction of inspired oxygen (Fio2). microbials for 14 days.
His relevant laboratory values are as follows: SCr
1.0 mg/dL, CD4+ count 100/mm3, LDH 550 IU/L,
Pao2 80 mm Hg, Paco2 40 mm Hg, and WBC 4 x
103 cells/mm3. The patient has a sulfa allergy and
a glucose-6-phosphate dehydrogenase deficiency.
Which regimen for presumed Pneumocystis jiroveci
pneumonia (PJP) is most appropriate?
A. Trimethoprim/sulfamethoxazole 15–20 mg/
kg intravenously, divided every 6 hours, plus
prednisone 40 mg twice daily.
B. Pentamidine 4 mg/kg intravenously every 24
hours alone.
C. Primaquine 30 mg orally once daily plus
clindamycin 600 mg intravenously every 8
hours alone, plus prednisone 40mg twice daily.
D. Atovaquone 750 mg orally every 12 hours plus
prednisone 40 mg twice daily.
8. A 50-year-old woman with acute myeloid leukemia

is admitted for induction therapy. During the
patient’s clinical course, she develops respiratory
distress, for which she is admitted to the medical
ICU. She is found to have neutropenic fever
and is empirically treated with meropenem plus
gentamicin plus vancomycin. On day 5 of empiric
therapy, blood cultures are growing pan-sensitive
E. coli. The patient’s relevant laboratory values and
vital signs are as follows: blood pressure 115/70 mm
Hg, heart rate 84 beats/minute, temperature 101.2°F,
and absolute neutrophil count less than 50 cells/
mm3. Which is the most appropriate antimicrobial
regimen for the patient?
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I. QUALITY IMPROVEMENTS – AMERICAN COLLEGE OF SURGEONS NATIONAL SURGICAL

QUALITY IMPROVEMENT PROGRAM AND THE SURGICAL CARE IMPROVEMENT PROJECT
NATIONAL HOSPITAL INPATIENT QUALITY MEASURES
A. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) provides
general best practice guidelines, and the Surgical Care Improvement Project (SCIP) provides quality
measures for specific surgical procedures (cardiac surgery, hip arthroplasty, knee arthroplasty, colon surgery,
hysterectomy, and vascular surgery).
1. ACS NSQIP also provides a surgical risk calculator that, depending on the type of surgery and the
patient’s baseline characteristics, can generate estimated risks of complications, which include
pneumonia, cardiac complications, surgical site infections (SSIs), urinary tract infections (UTIs), venous
thromboembolism, renal failure, discharge to a rehabilitation facility, and death. (This risk calculator can
be accessed at http://riskcalculator.facs.org/.)
2. Specific SCIP measures can be found through the following link: www.jointcommission.org/
specifications_manual_for_national_hospital_inpatient_quality_measures.aspx. Of note, starting in
January 2015, SCIP reporting underwent several changes. The most pertinent changes for pharmacists
are documented as follows.
a. Retirement of traditional chart abstract SCIP measures SCIP INF-1 (prophylactic antimicrobial
within 1 hour of incision); SCIP INF-2 (prophylactic antibiotic selection for surgical patients);
SCIP INF-3 (discontinuation of prophylactic antibiotic within specified time period); SCIP
INF-4 (controlled postoperative blood culture); and SCIP INF-9 (removal of urinary catheter by
postoperative day 2). In addition, each of the sub-measures under SCIP INF-1, INF-2, and INF-3 for
the various surgery types were retired.
b. eSCIP-9 (removal of urinary catheter by postoperative day 2) and eSCIP INF-1 (prophylactic
antimicrobial within 1 hour of incision), together with all the sub-measures for each type of surgery,
will be reported by electronic methods.
c. Despite the retirement of several SCIP measures, and thus the need to formally report the data
associated with each measure, the practices described within the retired SCIP measures still
represent best practices and should be continued. The rationale provided by the Joint Commission
for the retirement of INF-1, 2, 3, and 9 stated that this was because of consistently high compliance
rates. Rationale for the temporary suspension of INF-4 is to the possibility that the measure is no
longer consistent with clinical guideline recommendations, and the suspension allows time for the
agency to evaluate the issue.
B. Prevention of SSIs – ACS NSQIP and SCIP Measures

1. Epidemiology and clinical significance
a. More than 290,000 SSI cases occur each year.
b. Mortality rate is 2–12 times higher than in surgical patients without SSIs.
c. SSIs account for $4–$10 billion in direct costs.
2. Risk factors for SSIs: Advanced age, obesity, hyperglycemia, dyspnea, hypoxia, smoking, alcoholism,
recent radiotherapy, preoperative albumin less than 3.5 mg/dL, total bilirubin greater than 1.0 mg/dL,
trauma/shock, transfusion, hypothermia, inadequate skin preparation, abdominal surgery, contaminated
procedures, cancer, emergency surgery, staphylococcal colonization, and prolonged procedure
3. The Centers for Medicare & Medicaid Services (CMS) no longer provides reimbursement to providers
for the treatment of SSIs after cardiac, bariatric, or orthopedic surgical procedures.
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4. Prevention strategies: Pharmacy-specific

a. Preoperative
i. Control serum blood glucose in patients with diabetes (ACS/NSQIP measure)
ii. Administer prophylactic antibiotics within 1 hour before surgery (vancomycin and
fluoroquinolones should be administered within 2 hours before surgery) – ACS/NSQIP and
SCIP measure
iii. Select the appropriate prophylaxis – See Table 1 (no longer a reportable SCIP measure).
iv. Adjust dose of antibiotics for obesity – See Table 2 for suggested dosing (ACS/NSQIP measure).
b. Intraoperative
i. Re-dose antibiotics, if necessary – See Table 2 for dosing schedule during surgery (ACS/NSQIP
measure).
ii. In general, antibiotics with short half-lives should be re-dosed at a frequency of 2 times the
half-life of the agent.
iii. Goal of re-dosing is to maintain bactericidal concentrations throughout the operation. May be
prudent to consider re-dosing prophylaxis intraoperatively if large amounts of fluids and/or
transfusions are being administered
iv. Maintain normothermia
c. Postoperative
i. Monitor and maintain glucose concentrations less than 200 mg/dL in cardiothoracic surgery
patients – ACS/NSQIP measure. Of note, at the time of writing, SCIP had suspended the
required measure for post-cardiac surgery glucose; however, in the early release of the 2016
guidelines, it is included as a core measure.
ii. Discontinue prophylactic antibiotics within 24 hours after non-cardiac surgery and within 48
hours after cardiac surgery. Drains are not sufficient reason to continue prophylactic antibiotics
– ACS/NSQIP measure
5. Management of SSIs: See Infectious Disease I chapter.
Table 1. Prophylactic Antibiotic Regimens for Surgery

Alternative Prophylaxis in Patients
Type of Surgery Recommended Prophylaxis with β-Lactam Allergies
• Coronary artery bypass
grafting
• Other cardiac surgery
• Cefazolin • Vancomycin
• Vascular surgery
• Cefuroxime • Clindamycin
• Hip arthroplasty
• Knee arthroplasty
• Neurosurgery
• Cefazolin • Vancomycin
• Thoracic surgery
• Ampicillin/sulbactam • Clindamycin
• Clindamycin or vancomycin +
• Gastroduodenal surgery • Cefazolin aminoglycoside or fluoroquinolone
or aztreonam
• Cefotetan or cefoxitin or • Clindamycin + aminoglycoside or
• Colorectal surgery ampicillin/sulbactam or ertapenem fluoroquinolone or aztreonam
• Metronidazole + cefazolin or • Metronidazole + aminoglycoside or
cefuroxime or ceftriaxone fluoroquinolone
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Table 1. Prophylactic Antibiotic Regimens for Surgery (continued)

Alternative Prophylaxis in Patients
Type of Surgery Recommended Prophylaxis with β-Lactam Allergies
• Clindamycin or vancomycin +
• Abdominal hysterectomy aminoglycoside or fluoroquinolone
• Cefotetan or cefoxitin or
• Vaginal hysterectomy or aztreonam
ampicillin/sulbactam
• Biliary tract surgery • Metronidazole + aminoglycoside or
fluoroquinolone
Table 2. Recommended Dose and Dosing Interval for Commonly Used Antibiotics for Surgical Prophylaxis
Antimicrobial Recommended Dose in Adults Dosing Interval (hr)a
Ampicillin/sulbactam 3g 2
Ampicillin 2g 2
Aztreonam 2g 4
Cefazolin 2 g, 3 g for patients weighing ≥ 120 kg 4
Cefuroxime 1.5 g 4
Cefoxitin 2g 2
Cefotetan 2g 6
Ceftriaxone 2g N/Ab
Ciprofloxacin 400 mg N/Ab
Clindamycin 900 mg 6
Ertapenem 1g N/Ab
Gentamicin 5 mg/kg of actual or adjusted body weight N/Ab
Levofloxacin 500 mg N/Ab
Metronidazole 500 mg N/Ab
Vancomycin 15 mg/kg N/Ab
a
With presumed normal renal function.
b
One dose of the antibiotic should suffice for the duration of most surgical procedures.
N/A = not applicable.
C. Prevention of Catheter-Associated Urinary Tract Infections (CAUTIs) – ACS NSQIP Measures

1. Definition – Centers for Disease and Prevention (CDC) – See Figure 1 (updated in 2015).
2. Epidemiology and clinical significance. UTIs represent 30%–40% of all nosocomial infections. Up to
80% of UTIs are caused by urinary catheterization.
a. More than 5% of postoperative patients will experience a UTI.
b. CAUTIs account for $300–$400 million in additional health care costs.
c. CMS no longer provides reimbursement to providers for the treatment of CAUTIs.
3. Risk factors: Increased duration of catheterization, female, diabetes mellitus, bacterial colonization of
drainage bag, older age, and azotemia
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4. Prevention strategies
a. Minimize the use of prolonged urinary catheters. SCIP measures require the removal of urinary
catheters by postoperative day 2.
b. Pharmacists may provide reminders as part of a multidisciplinary effort to minimize the placement
and duration of urinary catheters.
c. Strategies that should NOT be considered:
i. Routine use of silver or antibiotic-impregnated catheters. According to the CDC, silver or
antibiotic-impregnated catheters can be considered if a comprehensive strategy to reduce
CAUTI rates has failed. The ACS/NSQIP best practices guidelines suggest that use of
antimicrobial urinary catheters can be considered for high-risk patients, such as those who may
require prolonged (greater than 7–10 days) catheterization.
ii. Addition of antibiotics to drainage bag
iii. Use of systemic antibiotic prophylaxis
iv. Routine screening or treatment of asymptomatic bacteriuria
v. Bladder irrigation with antibiotics
5. Management of CAUTIs: See Infectious Disease I chapter.
No
Urinary catheter in place > 2 days within 48 hr before event Not a CAUTI
Yes
Has the urinary catheter been removed?
Yes No
Was catheter removed

within 48 hr before event
Yes No
At least 1 of the following signs and symptoms Not a CAUTI

• Fever (temp > 38°C)
At least 1 of the following signs and symptoms
• Urgencya
• Fever (temp > 38°C)
• Frequencya
• Suprapubic tendernessa
• Dysuriaa
• Costovertebral angle pain or tendernessa
• Suprapubic tenderness
• Costovertebral angle pain or tendernessa
No Yes No
Not a CAUTI • Positive urine culture > 105 Not a CAUTI

No
CFU/mL with no more than Not a CAUTI
two species of organisms
Yes
CAUTI
Figure 1. Diagnosis of catheter-associated urinary tract infection according to CDC criteria.

With no other recognized cause.
a
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Patient Case
1. C.L is a 55-year-old man admitted to the surgical ICU after exploratory laparotomy for duodenal perforation
and peritonitis. The patient was transferred from the operating room to the surgical ICU with a urinary catheter
in place. On day 4 of the surgical ICU stay, the patient is extubated, and his urinary catheter is removed. On day
6 of the surgical ICU stay, the patient develops signs and symptoms of UTI with fever, urgency, and frequency.
Urinalysis reveals no nitrites or leukocyte esterase. Urine cultures show 100,000 CFU/mL of E. coli. You are
asked by the quality officer of the surgical ICU to discuss this case and determine whether this patient will
qualify for the definition of CAUTI according to CMS criteria. Which statement regarding the diagnosis of
CAUTI in this patient is most appropriate?
A. Qualifies for definition of CAUTI because the patient is symptomatic and has positive cultures.
B. Does not qualify for definition of CAUTI because the patient had a negative urinalysis.
C. Qualifies for definition of CAUTI because the patient is symptomatic and had recent urinary catheter.
D. Does not qualify for definition of CAUTI because the catheter was removed 2 days before symptoms.
D. Prevention of Catheter-Related Bloodstream Infections – ACS NSQIP

1. Definition (CDC): Updated in 2015 – Must satisfy both “a.” and “b.” criteria
a. Laboratory-confirmed bloodstream infection
i. Definition 1: A recognized pathogen (not a common skin contaminant) found in one or more
blood cultures AND the organism is not related to an infection at a separate site
ii. Definition 2: At least one sign or symptom of infection (temperature greater than 100.4°F
[38°C], chills, hypotension) AND a common skin flora is cultured from two or more blood
samples AND organism is not related to an infection at a separate site
b. Central line placed for greater than 2 days on the date of event and central line must be present or
be removed within 24 hours of blood cultures being obtained
2. Epidemiology and clinical significance
a. Incidence of catheter-related bloodstream infections: 2.7–7.4 infections per 1000 catheter-days
b. Accounts for 14,000–28,000 deaths per year
c. Increases mean length of stay (LOS) by 7 days
d. CMS no longer provides reimbursement to providers for the treatment of catheter-related bloodstream
infections.
3. Risk factors
a. Patient factors: Male, diabetes, hypotension, neutropenia, parenteral nutrition, prolonged
hospitalization before catheter placement
b. Catheter-related factors: Internal jugular or femoral vein placement site (compared with subclavian
vein), heavy microbial colonization at insertion site, use of non-tunneled catheters, inadequate
catheter care, prolonged duration of venous catheterization
4. Prevention strategies
a. Use appropriate techniques for catheter insertion (e.g., skin preparation and maximal sterile barrier
precautions) and management (e.g., daily site care, routine site evaluation for local erythema).
Minimize the use of central venous catheters. Pharmacists may provide reminders as part of a
multidisciplinary effort to minimize the placement and duration of venous catheters.
b. Consider antibiotic lock therapy in patients with limited venous access or a history of catheter-
related bloodstream infections.
c. Do not routinely use systemic antibiotic prophylaxis.
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d. Antimicrobial/silver-impregnated catheter should be considered in patients with an anticipated

catheter duration greater than 5 days if rates of catheter-related bloodstream infections have not
decreased despite the implementation of a comprehensive prevention strategy.
5. Management: See Infectious Diseases I chapter.
II. BACTERIAL MENINGITIS
A. Epidemiology
1. Bacterial meningitis is a neurologic emergency involving mild to severe inflammation of the meningeal
layers encasing the central nervous system (CNS). The CSF is intimate to the meninges, serving as
pathogen media and diagnostic fluid.
2. Bacterial meningitis is community acquired or health care associated, the latter of which is usually
associated with neurotrauma or neurosurgical procedures.
3. Community-acquired bacterial meningitis has an annual incidence in adults of about 2 cases per 100,000
people. The incidence has been decreasing in recent years (2 cases per 100,000 in 1998 to 1.38 cases per
100,000 in 2006; 31% decrease), likely because of increased vaccination. The incidence of nosocomial
bacterial meningitis varies depending on the mechanism of neuro-anatomic disruption and ranges from
1.5% of patients undergoing craniotomy to 25% of post-trauma patients with basilar skull fracture.
4. Delayed CSF sterilization beyond 24 hours is a risk factor for subsequent neurologic sequelae, including
intracranial hypertension, seizures, and permanent neurologic deficit. Clinical presentations of septic
shock, altered mental status, and seizures are associated with worse outcomes. Additional complications
include respiratory failure and hyponatremia.
5. Crude mortality for community-acquired meningitis is 19%–37%, whereas mortality for health care–
associated meningitis is generally lower, particularly if associated with a reversible procedure or
removable device.
B. Definitions
1. Community-acquired meningitis is an infection unrelated to a neurosurgical procedure, neurotrauma,
or hospitalization.
2. Health care–associated or nosocomial meningitis is an infection related to invasive procedures,
including craniotomy, internal or external ventricular catheters, lumbar puncture, intrathecal medication
administration, and spinal anesthesia. Additional causes include complicated closed or open cranial
trauma, traumatic brain injury, and hematogenous spread in patients with hospital-acquired bacteremia.
C. Diagnosis
1. The clinical diagnosis of meningitis is nonspecific and difficult to distinguish from that of other
infections. Although headache, fever, neck stiffness, and altered mental status are present in almost 95%
of patients with community-acquired meningitis, fever and a decreased level of consciousness are the
most consistent clinical features in patients with health care–associated meningitis.
2. Lumbar puncture or other method (e.g., from existing drain or shunt) to sample CSF for cell count and
analysis, as well as Gram stain and culture, is necessary for definitive diagnosis. Neuroimaging with
head CT to detect prelumbar brain shift and risk of brain herniation should be done before lumbar
puncture in patients with suspected cranial mass (e.g., immunosuppressed; papilledema, history of CNS
disease, new-onset seizure, focal neurologic deficit).
a. Opening pressure during lumbar puncture is usually increased in bacterial meningitis.
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b. Cell count and fluid analysis

i. Community-acquired bacterial meningitis can be differentiated from other causes of meningitis
(e.g., viral; aseptic). In general, bacterial meningitis is associated with CSF that is predominantly
neutrophilic and has lower glucose concentration. Individual strong predictors of bacterial
meningitis include:
(a) CSF glucose less than 34 mg/dL
(b) Ratio of CSF to blood glucose less than 0.23
(c) CSF protein greater than 220 mg/dL
(d) CSF leukocyte count greater than 2000 cells/mm3
(e) CSF neutrophil count greater than 1180 cells/mm3
ii. The diagnostic utility of CSF cell count and fluid analysis in health care–associated meningitis
is unknown but is likely limited because of concomitant reasons for local inflammation related
to devices or recent procedures. Elevated CSF lactate concentration may be useful to distinguish
meningitis from other infectious sources.
c. Gram stain and culture: Bacteriologic examination of CSF can provide rapid and reliable identification
of the causative pathogen(s). Although CSF cell count and analysis is the diagnostic foundation for
community-acquired meningitis, CSF culture is the most specific test for health care–associated
meningitis.
D. Management and Treatment

1. Appropriate empiric antibiotic therapy administered intravenously, targeted against likely pathogens, and
guided by local antibiotic susceptibility patterns should be initiated as soon as possible after bacterial
meningitis is suspected. See Table 3 for common pathogens and recommended empiric therapy.
2. Antibiotic dosing and administration strategies should be chosen to optimize CSF concentrations relative
to bacterial minimum inhibitory concentration (MIC) and antibiotic pharmacodynamic (PD) properties.
Although meningeal inflammation may promote CSF penetration, data are inconsistent.
3. Gram stain can be used to broaden bacterial coverage, but final culture should be reserved for antibiotic
de-escalation and definitive antibiotic regimen.
4. Role of corticosteroids
a. Adjunctive corticosteroids may improve outcomes by reducing reactive meningeal inflammation
and neurologic sequelae related to antibiotic induced bacterial lysis.
b. Conflicting results are published regarding the effects of systemic corticosteroids on neurologic
sequelae and mortality among patients with bacterial meningitis.
c. Studies from high-income countries tend to suggest that systemic corticosteroids decrease or trend
toward a decrease in mortality and neurologic sequelae.
d. The outcome benefit associated with systemic corticosteroids seems most pronounced with patients
with S. pneumoniae meningitis. However, because corticosteroids must be administered before the
receipt of antimicrobials, it is unlikely that clinicians will know the etiology of the disease when
making the decision for steroids.
e. The Infectious Diseases Society of America (IDSA) guidelines recommend administering
dexamethasone 0.15 mg/kg every 6 hours for up to 96 hours, with the first dose administered 10–20
minutes before, or at least concomitant with, the first dose of antimicrobial therapy. The IDSA
guidelines also recommend for continuation of dexamethasone only if cultures show the presence of
S. pneumoniae, although this recommendation is not supported by strong clinical evidence.
5. Health care–associated meningitis
a. See Table 3 for empiric treatment of health care–associated meningitis.
b. In patients with CSF shunts, removal or replacement of drains or catheters should be considered.
CSF shunt replacement should not be done until after at least 7 days of appropriate antibiotic therapy.
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c. In selected patients with bacterial meningitis after placing a CSF shunt, the IDSA recommends direct
instillation of antimicrobial agents intraventricularly through either an external ventriculostomy or
shunt reservoir. This practice should only be considered in patients with pathogens that are difficult
to eradicate or for those who cannot undergo the surgical component of therapy. See Table 4 for
selected antimicrobial intraventricular dosing.
6. Definitive antibiotic therapy can be determined according to finalized cultures and susceptibility results.
In general, definitive therapy should entail choosing the therapy with the most appropriate spectrum of
activity and an adequate penetration into the CSF. Therapy should be continued for at least 7 days in
all patients with meningitis. S. pneumoniae should be treated for 10–14 days and gram-negative bacilli,
Listeria monocytogenes, and S. aureus for at least 21 days. CSF should be negative for S. aureus for at
least 10 days before shunt replacement.
Table 3. Common Pathogens Seen in Different Bacterial Meningitis Populations and the Corresponding Recommended
Empiric Therapy
Patient Group Common Pathogens Recommended Empiric Therapy
Community Acquired
Vancomycin + third-generation
18–50 yr N. meningitis, S. pneumoniae
cephalosporin (e.g., ceftriaxone)
N. meningitis, S. pneumoniae, Vancomycin + third-generation
> 50 yr or any age with
L. monocytogenes, H. influenzae, aerobic cephalosporin (e.g., ceftriaxone) +
predisposing conditiona
GNB (e.g., E. coli) ampicillin
Health care–associated or nosocomial
Basilar skull fracture
S. pneumoniae; H. influenzae; Vancomycin + third-generation
(communication with
group A β-hemolytic streptococci cephalosporin (e.g., ceftriaxone)
sinuses or oropharynx)
S. aureus, CoNS, aerobic enteric (e.g., E.
Vancomycin + cefepime or ceftazidime
Penetrating trauma coli) and non–lactose-fermenting (e.g., P.
or meropenem
aeruginosa) gram-negative bacilli
Aerobic enteric (e.g., E. coli) and non–
Vancomycin + cefepime or ceftazidime
Post-neurosurgery lactose-fermenting (e.g., P. aeruginosa)
or meropenem
gram-negative bacilli, S. aureus, CoNS
Aerobic enteric (e.g., E. coli) and non–
lactose-fermenting (e.g., P. aeruginosa) Vancomycin + cefepime or ceftazidime
CSF shunt
gram-negative bacilli, S. aureus, or meropenem
Propionibacterium acnes
a
Altered immune status, alcoholism.
CoNS = coagulase-negative staphylococci; GNB = gram-negative bacteria.
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Table 4. Selected Antibiotic CSF Penetration and Dosages for Meningitis

CSF Penetration,
Agent % of Serum Concentration Dosage for Meningitis
Conventional: 10–15 mg/kg IV q8–12hr
Amikacin Low Extended interval: 20–25 mg/kg IV once daily
Intraventricular: 30 mg QD
Ampicillin 13–14 2 g IV q4hr
Cefazolin 8–15 2 g IV q8hr
Cefepime 10–20 2 g IV q8hr
Cefotaxime 10–12 2 g IV q4hr
Ceftazidime 30–40 2 g IV q8hr
Ceftriaxone 8–12 2 g IV q12hr
Ciprofloxacin 20–25 400 mg IV q8hr
Colistin Low Intraventricular: 10 mg QD
Meropenem 6–21 2 g IV q8hr
Nafcillin 1–2.5 2 g IV q4hr
Not recommended because of low penetration of
Piperacillin/tazobactam 20–30
tazobactam
Conventional 2–3 mg/kg IV q8–12hr
Tobramycin 10–20 Extended interval: 5–7 mg/kg IV QD
Intraventricular 10–20 mg QD
15–20 mg/kg IV q8–12hr
Vancomycin 30
Intraventricular 10–20 mg QD
IV = intravenous(ly); q = every; QD = once daily.
Patient Case
2. H.K. is a 42-year-old woman who presents with her husband to the emergency department from home with
mental status changes, lethargy, and a temperature of 102.9°F (39.4°C). Her husband reports that she had
a severe headache 24 hours earlier. She has no significant medical history. Diagnostic workup results are
highly suggestive of meningitis. A lumbar puncture is performed, during which a high initial pressure is
noted. Which intervention would be best initially for H.K.?
A. Administer dexamethasone 0.15 mg/kg intravenously.
B. Await laboratory and microbiologic analysis.
C. Initiate empiric ceftriaxone and vancomycin.
D. Initiate empiric ampicillin, cefepime, and vancomycin.
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III. ANTIMICROBIAL STEWARDSHIP
A. Goals: To optimize clinical outcome while minimizing unintended consequences of antimicrobial use, which
include the emergence of antimicrobial resistance and adverse drug reactions. In addition, a responsible
approach to the use of antimicrobial agents should reduce the overall costs associated with treatment.
1. Antibiotics are the second most common class of drugs that cause adverse effects.
2. Antibiotics are the most common class of medication to be associated with prescribing errors.
3. Minimizing antimicrobial resistance by optimizing therapy should lead to measurable benefits on the
patient level because studies have shown the negative effect of antimicrobial resistance on several clinical
outcomes.
B. Definition: Multidisciplinary coordinated interventions designed to improve and measure the appropriate use
of antimicrobial agents to promote the selection of optimal antimicrobial drug regimen, including dosing,
duration, and route of administration.
1. Core members of a multidisciplinary antimicrobial stewardship team should include an infectious
diseases physician, a clinical pharmacist, a clinical microbiologist, an information systems specialist, an
infection control professional, and a hospital epidemiologist.
2. Broad-spectrum antimicrobials are often necessary in the ICU to provide early effective therapy. However,
continued use of broad-spectrum antimicrobials may lead to the selection of pathogenic organisms (i.e.,
Clostridium difficile, Candida spp.), nephrotoxicity, and the emergence of resistance.
C. Critical Care Pharmacists – Well positioned to provide guidance on antimicrobial therapy, including expedited
selection of appropriate initial agents, aggressive dosing to optimize PD, interpretation of microbiological
evidence, appropriate de-escalation of antimicrobials, monitoring of response and potential adverse effects,
and determination of the appropriate treatment duration
1. Critical care pharmacists could either have an active role as a member of a multidisciplinary antibiotic
stewardship team or serve in many of the different roles and activities of antibiotic stewardship.
2. Core activities that can be pursued through formal pathways or everyday clinical interventions
a. Education with active intervention – Interpretation of rapid identification tests and susceptibility
testing
b. Guidelines and clinical pathway development
c. Streamlining or de-escalation of therapy
i. Shortening therapy duration
ii. Discontinuing unnecessary antimicrobials
d. Dose optimization
i. Application of pharmacokinetic (PK)/PD principles
ii. Dose adjustments based on organ function
e. Parenteral to oral conversion
3. Support from microbiology laboratory and electronic medical record system surveillance and decision
support may further enhance stewardship efforts.
D. Two Strategies, Which Could Be Used Synergistically Together

1. Prospective audit with intervention and feedback (“back-end” strategy)
a. Allows flexibility and minimizes delay in administering therapy
b. The most successful strategy involves direct communication with treating physicians and required
documentation for acceptance of recommendation or rationale for denial.
2. Formulary restriction and preauthorization (“front-end” strategy).
a. May be resource-intensive, and prescribers may feel a loss of autonomy
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b. Initial choices of antimicrobials may be optimized through consultation with infectious disease
experts.
c. Antimicrobial cycling: An example of formulary restriction in which there is a scheduled removal
and substitution of a specific antimicrobial or an antimicrobial class. It is an effort to minimize
antimicrobial selection pressures. Evidence is insufficient to suggest that antimicrobial cycling
strategies are effective.
3. Regardless of the strategies used or the quality of clinical pathways, programmatic antibiotic stewardship
is not a substitute for clinical judgment.
4. Process measures and outcome measures should be used.
5. Both strategies should be supported by health care information technology and the electronic medical
record system. Clinicians should consult with information technology experts to optimize the use of
technology for screening and monitoring antibiotic stewardship activity to maximize scope while
minimizing manpower.
E. Effective Antimicrobial Stewardship Programs Can Be Financially Self-Supporting

1. Antimicrobials can account for up to 30% of hospital pharmacy budgets, with up to 50% of antimicrobial
use being inappropriate, leading to increased cost, increased selection of resistant pathogens, and
increased selection of opportunistic infections (OIs).
2. Several studies have shown the cost savings associated with an antimicrobial stewardship program.
However, most of these studies focused on antimicrobial costs, with little focus devoted to indirect costs
and implementation costs.
F. Evidence Supporting Antimicrobial Stewardship Efforts in Critically Ill Patients

1. Studies in this area have been limited by poor study design. However, most studies have reported a
decreased use in either antibiotics overall or a targeted class of antibiotics. Some studies have also
reported a decrease in key resistance rates.
2. Antimicrobial stewardship strategies used in the studies have varied widely, including restriction, formal
infectious disease physician consultation, protocols for de-escalation, implementation of computer-
assisted decision support, and formal reassessments of the empiric antibiotics by a stewardship team.
The compensatory overuse of another class of antibiotics has been reported when attempts to restrict a
different class of antibiotics were implemented.
IV. RAPID DIAGNOSTIC TESTS
A. Rationale
1. There is an association between delay in administration of appropriate antimicrobials and decreased
survival.
2. Broad-spectrum antimicrobials are usually used in severe infections to ensure that all potential pathogens
are covered.
3. Rapid diagnostic tests may assist in de-escalation efforts in an attempt to practice antimicrobial
stewardship. Critical care pharmacists are appropriate advocates for the appropriate use of antimicrobials
according to the results of rapid diagnostic tests.
4. In many cases, the implementation of rapid diagnostic tests may be cost-neutral, or even constitute a cost-
savings, when antimicrobial stewardship efforts leading to decreased consumption of antibiotics occur.
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B. Early Pathogen Identification from Positive Bloodstream Cultures

1. All discussed methods try to shorten the time from blood culture positivity to species identification
or susceptibility testing. Traditional pathogen identification and susceptibility testing can take 72–96
hours. Early pathogen identification techniques seek to provide clinically actionable information within
the first 24 hours from the time of culture positivity. See Table 5 for examples of rapid diagnostic tests,
corresponding targets, and respective turnaround times.
2. Most of these techniques, when combined with antibiotic stewardship efforts, lead to significant
reductions in health care costs and improvements in clinical outcomes. Many of these were single-center
studies, which makes clinical applicability questionable. The overall impact of the implementation of
rapid diagnostic tests in a single institution is determined by several factors.
a. Epidemiology of targeted organisms
b. Presence and actions of existing antimicrobial stewardship teams
c. Current clinician prescribing patterns
d. Patient population
3. The inability to detect polymicrobial infections is a common limitation to most of the techniques
described.
4. Newer methods using whole blood (vs. blood culture medium or agar plates) are being developed, but
none is currently U.S. Food and Drug Administration (FDA) approved (LightCycler SeptiFast, SepsiTest,
T2Candida).
5. Some of the technology discussed has been developed for respiratory cultures, but the clinical adaptation
in that arena is considerably less than that for blood cultures.
6. Application of rapid diagnostic tests that detect genetic encoding of resistance mechanisms requires
further education and guidelines to assist clinicians in choosing the proper therapy because traditional
susceptibility results are not available. See Table 6 for a reasonable approach based on the detection of
resistance genes and species.
7. Peptide nucleic acid (PNA) fluorescent in situ hybridization (FISH)
a. Mechanism: Targets species-specific ribosomal RNA from positive blood cultures
b. Sensitivity and specificity: 96%–100%
c. Limitations: Does not provide antimicrobial sensitivity data. Currently available FISH products
are only used for species identification; however, recently, the FDA approved a new product that
could detect the mecA gene for detecting the presence of methicillin resistance. This product is not
currently commercially available.
d. Application
i. Separates Staphylococcus aureus from possible skin flora contamination of coagulase-negative
staphylococci (CoNS).
ii. Differentiates Enterococcus faecium (which is often resistant to ampicillin and vancomycin)
from Enterococcus faecalis.
iii. Identifies fluconazole-sensitive Candida spp. for patients empirically treated with echinocandins.
iv. Detects Pseudomonas versus non-Pseudomonas gram-negative spp. in patients treated with
combination gram-negative therapy.
e. Studies
i. A retrospective study evaluating the outcome and economic benefit of PNA FISH methods for the
early differentiation of CoNS and S. aureus bacteremia in clinical practice showed a significant
cost savings and a decrease in median LOS. Of note, the PNA FISH results were combined with
the efforts of an antimicrobial therapy team. Similar results have been shown with PNA FISH
implementations for other pathogens, including Enterococcus spp. and Candida spp. These
results are in contrast to those of another study that evaluated the pre- and post-staphylococci
PNA FISH implementation results without the use of an antimicrobial stewardship team. This
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study found no significant effects on patient LOS or vancomycin use. This shows that rapid
identification tests are probably beneficial only when combined with educational efforts and
prospective alerts to notify clinicians of the clinical applicability of the test results.
ii. In a prospective randomized controlled study in which patients were randomized to early
notification of PNA FISH results for CoNS or S. aureus within 3 hours or usual care, intervention
was associated with decreased mortality, decreased antibiotic use, and decreased LOS. The
most pronounced benefits occurred in critically ill patients.
8. Mass spectroscopy: Matrix-assisted laser desorption-ionization/time of flight (MALDI-TOF)
a. Mechanism: Mass spectroscopy is compared with library standards for identifying pathogen species
and/or resistance mechanisms.
c. Limitations
i. Similar to PNA FISH, no antimicrobial susceptibility is reported; however, the technology
could detect genes encoding resistance. MALDI-TOF for resistance genes is currently not
commercially available.
ii. Cannot be used for polymicrobial cultures
iii. No library is available for unusual organisms, though pathogen libraries are consistently being
updated.
d. Application: Potentially wider clinical applicability than PNA FISH (which is limited by the
availability of specific tests for certain pathogens) with early identification of many more pathogens.
Additional library standards for different pathogens are continually being added.
e. Studies: This strategy has been evaluated in several studies. In a before-and-after study of MALDI-
TOF implementation, a shortened time to pathogen identification and a decreased in LOS, recurrent
infections, and mortality were seen. Of note, the implementation of MALDI-TOF included
communicating the results to the treatment clinicians by an antimicrobial stewardship team with
evidence-based antibiotic recommendations.
9. Polymerase chain reaction (PCR)-based detection systems
a. MRSA PCR test
i. Mechanism: Novel multiplex real-time assay for mecA gene
ii. Sensitivity and specificity: 98%–100% for MRSA and methicillin-sensitive S. aureus (MSSA)
identification
iii. Application: Earlier de-escalation of anti-MRSA antimicrobials and earlier appropriate
treatment with antistaphylococcal penicillin (oxacillin, nafcillin) for MSSA
iv. Studies: In a before-and-after study, implementation of the MRSA PCR test resulted in reduced
time to appropriate therapy and duration of unnecessary MRSA coverage. In addition, the mean
hospital costs were decreased, and there was a trend toward decreased LOS. In a very similar
study, the combination of the MRSA PCR test with antimicrobial stewardship efforts resulted
in significant decreases in LOS and cost and a trend toward decreased mortality (18% vs. 26%).
b. FilmArray system
i. Mechanism: Uses multiplex PCR technology
ii. Sensitivity and specificity
(a) For species identification: Greater than 90%
(b) For resistance genes: 100% (currently only available for mecA - methicillin resistance; van
A/B - vancomycin resistance; Klebsiella pneumoniae carbapenemase [KPC] - carbapenem
resistance)
iii. Application: Earlier escalation or de-escalation of antimicrobial agents
iv. Studies: No studies regarding the clinical effects of FilmArray implementation are available.
However, studies have shown an earlier time to pathogen identification.
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10. Nanoparticles: Verigene blood culture test

a. Mechanism
i. Direct detection from positive blood culture medium using nanoparticle technology
ii. Nucleic acid extraction and array hybridization
b. Most developed commercially available product with resistance gene detection
c. Sensitivity and specificity: 93%–100%
d. Studies: Currently, most studies are limited to in vitro evaluations, which showed high levels of
accuracy and decreased time to pathogen and resistance mechanism identification. Limited clinical
evidence; however, two small single-center studies have evaluated the use of Nanosphere technology
to augment clinical decisions. These studies showed a decrease in time to appropriate antimicrobials,
in addition to decreased LOS and overall cost.
11. Chromogenic media
a. Mechanism
i. Microbiological media used to identify different microorganisms by color production
ii. Growth media use enzyme substrates that release colored dyes on hydrolysis, with a wide range
of enzymes that can be targeted
iii. Potential advantage of being able to detect polymicrobial growth
c. Limitations
i. Many different companies make different chromogenic agar media (Brilliance, ChromID,
CHROMagar). Slight differences in sensitivity and specificity were seen in studies; however, all
were within acceptable ranges.
ii. Time to identification is longer than with other rapid diagnostic tests.
iii. Different manufacturers’ chromogenic agar produces different colors for positive identification.
Readers of chromogenic agar should be sufficiently trained and familiar with the product used
by the local institution.
d. Application
i. Isolation of S. aureus from other Staphylococcus spp.
ii. Detection of methicillin resistance among S. aureus
iii. Detection of vancomycin resistance
iv. Detection of specific Enterobacteriaceae: Salmonella, E. coli O157, extended-spectrum
β-lactamase (ESBL) production
v. Differentiation of different Candida spp.
vi. Detection of KPC
e. Studies: Many clinical studies have shown significant advantages over conventional culture media.
With the advent of newer technology and shorter detection times, the clinical applicability of
chromogenic media may be limited. However, few microbiology laboratories have implemented
rapid diagnostic methods because of the considerable upfront costs. Centers where chromogenic
media are being used may continue to rely on this technology.
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Table 5. Examples of Rapid Diagnostic Tests of Positive Blood Cultures and Their Characteristics
Detection Time
Assay Manufacturer/ Organisms/Antimicrobial After Positive Growth
Technology Trade Name Resistance Targets on Blood Culture
• AdvanDx/PNA S. aureus, CoNS, E. faecalis, E. faecium, 1.5 hr – PNA FISH
FISH, Traffic light E. coli, K. pneumoniae, P. aeruginosa, 20 min – QuickFISH –
PNA FISH
• AdvanDx/ C. albicans, C. glabrata, C. parapsilosis, Not currently available
QuickFISH C. tropicalis, C. krusei for Candida spp.
• BD GeneOhm/
Staph SR
PCR S. aureus, CoNS/mecA (methicillin) 1–2 hr
• Cepheid/Xpert
MRSA
Enterococcus spp., L. monocytogenes
S. aureus, S. agalactiae, S. pneumoniae,
S. pyogenes/mecA (methicillin), vanA/B
(vancomycin)
A. baumannii, H. influenzae, N. meningitidis, 1 hr – Direct from
PCR • BioFire/FilmArray
P. aeruginosa, E. cloacae, E. coli, K. oxytoca, blood culture media
K. pneumoniae, Proteus spp., S. marcescens/
KPC (carbapenem)
C. albicans, C. glabrata, C. krusei,
C. parapsilosis, C. tropicalis
• BioMérieux/ Several pathogens, including bacteria, yeast,
MALDI-TOF Vitek MS mold, mycobacteria/resistance mechanisms are 10–30 min
• Bruker/Microflex in developmenta
S. aureus, S. epidermidis, S. lugdunensis,
S. anginosus, S. agalactiae, S. pneumoniae,
S. pyogenes, E. faecalis, E. faecium,
Staphylococcus spp., Streptococcus spp.,
Micrococcus spp., Listeria spp./mecA
(methicillin), vanA (vancomycin), vanB
(vancomycin)
• Nanosphere/ 2 hr – Direct from
Nanoparticles E. coli, K. pneumoniae, K. oxytoca,
Verigene blood culture media
P. aeruginosa, S. marcescens, Acinetobacter
spp., Citrobacter spp., Enterobacter
spp., Proteus spp./CTX-M (ESBL), IMP
(carbapenemase), KPC (carbapenemase), NDM
(carbapenemase), OXA (carbapenemase), VIM
(carbapenemase)
Candida spp. in development
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Table 5. Examples of Rapid Diagnostic Tests of Positive Blood Cultures and Their Characteristics (continued)
Detection Time
Assay Manufacturer/ Organisms/Antimicrobial After Positive Growth
Technology Trade Name Resistance Targets on Blood Culture
S. aureus, MRSA, Enterococcus spp.,VRE,
S. agalactiae, E. coli (Shiga toxin, EC-O157),
Chromogenic Klebsiella spp., Proteus spp., Pseudomonas
• CHROMagar spp., Acinetobacter spp., Yersinia spp.; KPC 24–48 hr
media
(carbapenem), CTX-M (ESBL)
C. albicans, C. tropicalis, C. krusei
a
The mass spectrometry database of organisms is constantly changing and growing.
ESBL = extended-spectrum β-lactamase; KPC = Klebsiella pneumoniae carbapenemase; MALDI-TOF = matrix-assisted laser desorption-ionization/time
of flight; MRSA = methicillin-resistant S. aureus; NDM = New Delhi metallo-β-lactamase; PCR = polymerase chain reaction; PNA FISH = peptide nucleic
acid fluorescent in situ hybridization; VRE = vancomycin-resistant enterococci.
Reproduced with permission from: Goff DA, Jankowski C, Tenover F. Using rapid diagnostic tests to optimize antimicrobial selection in antimicrobial
stewardship programs. Pharmacotherapy 2012;32:677-87.
Table 6. Reasonable Empiric Treatment Approach Associated with Detection of Antimicrobial Resistance Encoding
Genes from Rapid Diagnostic Tests for Positive Blood Culturesa
Resistance Genes Species Recommended Therapy Alternative Therapy
• Cefazolin
• Oxacillin
mecA-negative S. aureus • Vancomycin (if allergic to
• Nafcillin
β-lactams)
• Daptomycin
mecA-positive S. aureus • Vancomycin • Linezolid
• Ceftaroline
• Vancomycin (if allergic to
vanA/B-negative E. faecalis • Ampicillin
β-lactams)
• Daptomycin • Linezolid
vanA/B-positive E. faecalis
• Ceftaroline
• Daptomycin (if allergic to
vanA/B-negative E. faecium • Vancomycin
vancomycin)
vanA/B-positive E. faecium • Daptomycin • Linezolid
• Carbapenems (ertapenem,
Enteric gram-negative
CTX-M (ESBL)a imipenem, meropenem, • Ceftazidime/avibactam
pathogens
ertapenem)
K. pneumoniae • Colistin
KPC a
and other enteric gram- • Tigecycline
negative pathogens • Ceftazidime/avibactam
K. pneumoniae • Colistin
NDM
and other enteric gram- • Tigecycline
carbapenemasea
negative pathogens
VIM or IMP • Colistin
P. aeruginosa
carbapenemasea • Aztreonam
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Table 6. Reasonable Empiric Treatment Approach Associated with Detection of Antimicrobial Resistance Encoding
Genes from Rapid Diagnostic Tests for Positive Blood Culturesa (continued)
Resistance Genes Species Recommended Therapy Alternative Therapy
• Colistin
OXA β-lactamasea P. aeruginosa
• Carbapenemb
• Colistin
OXA β-lactamase a
A. baumannii • Tigecycline
• Carbapenemb
a
Resistance mechanisms associated with gram-negative pathogens are more complicated. Often, there is more than one resistance mechanism. Hence, the
recommended therapies represent reasonable empiric approaches, before full antimicrobial susceptibility reports. However, therapy may be tailored to either
a broader or a narrower spectrum.
b
Carbapenem may have a higher MIC in the presence of OXA β-lactamase. If using carbapenem, may consider using maximal doses.
Patient Case
3. A 54-year-old man is admitted to the medical ICU with acute necrotizing pancreatitis. He is found to have
an infected pancreatic abscess, which is being treated with meropenem and vancomycin. Two weeks into
the course, the patient develops a fever and leukocytosis. He also becomes hemodynamically unstable and
oliguric. He is initiated on caspofungin empirically to cover for possible invasive candidiasis. Blood cultures
are obtained, which become positive with a preliminary result of yeast. This institution is equipped with PNA
FISH technology, which identifies the yeast as Candida parapsilosis on day 2 of therapy. The patient remains
hemodynamically unstable. Which is the most appropriate choice for this patient’s antifungal therapy?
A. Continue caspofungin while fungal susceptibilities are finalized.
B. Change to voriconazole 6 mg/kg every 12 hours.
C. Change to liposomal amphotericin 5 mg/kg/day.
D. Change to fluconazole 400 mg intravenously daily.
C. Early C. difficile Identification

1. Traditional methods for identifying C. difficile toxins (cytotoxin neutralization assay and rapid enzyme
immunoassays) attain a sensitivity of 60%–70%.
a. Usually targeting toxin A, toxin B, or both
b. Recommend up to three serial tests to improve sensitivity
2. Nucleic acid amplification methods (PCR and loop-mediated isothermal amplification)
a. Assays are targeting DNA sequence for the toxin A or toxin B gene.
b. Turnaround time: 1–3 hours
c. Sensitivity and specificity: 90%–96%
i. Because of increased sensitivity, the false-positive rates may be increased.
ii. As the prevalence of C. difficile decreases, the positive predictive value decreases, which may
lead to unnecessary overtreatment.
iii. Educational efforts should be made to discourage the practice of over-ordering C. difficile rapid
nucleic acid amplification tests. In addition, clinicians should be discouraged from ordering
serial tests, which was a common practice when enzyme immunoassays were used. Because
the sensitivity is sufficiently high, serial ordering only furthers the chance of false positivity.
D. Early Identification of Fungal Organisms

1. Up to 50% of patients with histopathologically proven invasive candidiasis have negative blood cultures.
2. Cultures for Aspergillus lack sensitivity and may require significant growth time.
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3. Biopsies are often not feasible in critically ill patients.

4. Surrogate markers of fungal infections are needed for early diagnosis and to avoid delays in treatment,
which have been associated with worsened outcomes.
5. β-d-Glucan
a. Found in the cell membrane of most fungal pathogens (except for Mucor and Cryptococcus).
Potentially a screening tool for Candida, Aspergillus, and Pneumocystis
b. Fungitell assay can detect β-d-glucan in serum and provide results within 2 hours.
c. Variable cutoffs are described in the literature for a positive result. A suggested cutoff for positive
results, as used in a recent study evaluating prophylactic and preemptive antifungal therapy in
critically ill patients, is greater than 80 pg/mL.
d. Considerable differences in sensitivity and specificity values have been seen in different populations.
e. Consistently high negative predictive values and low positive predictive values have been seen for
the diagnosis of invasive fungal infections, which suggests that it is best used as a screening-out tool
when the values are low. Low positive predictive value may occur because many clinical scenarios
could lead to false-positive results.
i. Exposure to β-d-glucan–containing surgical supplies and topical products
ii. Colonization with Candida
iii. Thrush and mucositis
iv. Cellulose membranes from dialysis filters
v. Bacterial infections
vi. Receipt of β-lactam antibiotics
f. When used as a tool to potentially initiate treatment, optimal results occur when two consecutive
tests are positive.
g. Non-specific fungal element makes interpretation difficult. May detect elements from Aspergillus,
Candida, and Pneumocystis. Does not detect different species
h. Has been evaluated in combination with clinical prediction scores for invasive candidiasis in
critically ill patients for initiating empiric antifungal therapy. When using β-d-glucan as a screening
tool, empiric echinocandin therapy does not result in any significant differences in clinical outcomes
compared with placebo.
6. Galactomannan
a. Cell wall component of Aspergillus spp.
b. Platelia enzyme immunoassay can detect galactomannan in serum or other sterile fluids
(bronchoalveolar lavage) within 4 hours.
c. Variable sensitivity and specificity, with generally better positive and negative predictive values for
the detection of Aspergillus in the patient population with hematologic malignancies than in the
solid organ transplant (SOT) population
d. False positives can occur with the simultaneous administration of certain β-lactam antibiotics
(piperacillin/tazobactam, amoxicillin/clavulanic acid) or the presence of other invasive mycoses
(Penicillium, histoplasmosis, blastomycosis).
7. Other Candida early diagnostic tools such as PCR, mannan, and d-arabitol require additional investigation
before wide clinical adaptation.
E. Procalcitonin (PCT)
1. An inflammatory biomarker that reflects host response to bacterial infections
2. PCT synthesis is up-regulated by bacterial toxins and certain bacterial proinflammatory mediators such
as interleukin (IL)-1b, IL-6, and TNFα (tumor necrosis factor alpha), but it is neutral to cytokines that are
normally released for viral infections such as interferon-γ. Usual concentrations of PCT are undetectable
(less than 0.05 ng/mL). However, on exposure to bacterial toxins, PCT is rapidly released within 2–4
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hours. The plasma half-life of PCT is 24 hours. Concentrations seen in the literature for infected patients
vary greatly; however, it appears that higher max concentration of PCT during infection correlates with
a higher incidence of mortality.
3. PCT is used in many roles, including the diagnosis and prognostication for sepsis and severe sepsis.
4. For clinical decisions regarding antibiotic use and duration, PCT has been evaluated for antibiotic
initiation, antibiotic cessation, and the combination of both strategies. These strategies assume PCT
availability from an institutional laboratory. If the PCT turnaround time is more than 24 hours, the
effects of minimizing antimicrobial treatment days may be limited.
5. According to current evidence, PCT should not routinely be measured in patients without signs and
symptoms of infection. The decision to initiate patients on antibiotics without signs and symptoms of
infection using PCT alone would probably lead to antimicrobial overuse and possible adverse effects
associated with antimicrobial therapy. In the largest PCT study of critically ill patients to date, 1200
patients were randomized to either a PCT alert strategy or a standard of care. For those randomized
to intervention, a PCT concentration greater than 1.0 mcg/L generated an alert that mandated clinical
intervention, which included microbiological cultures, additional radiologic assessment, and/or initiation
or expansion of antimicrobial coverage. Overall, this strategy did not lead to an improvement in mortality
or time to appropriate antibiotics. In contrast, patients experienced a greater need for mechanical
ventilation, prolonged ICU LOS, and prolonged antibiotic use.
6. In critically ill patients with signs and symptoms of infection, a baseline PCT (at the time of the
symptoms) should not be used to determine whether antibiotics should be initiated. The compliance rate
for withholding antibiotics for a low PCT in this scenario has consistently been low. The compliance rate
in clinical practice is likely even lower than that in clinical studies; however, this has not been evaluated.
If a baseline PCT is obtained, it should be used to trend the PCT for the possible early discontinuation
of antibiotics. In a study of patients with signs and symptoms of infections to determine whether a
PCT-guided strategy would limit the initiation of antibiotics, no difference in antibiotic use was seen.
However, this was probably because only 36% of clinicians were compliant with the recommendation to
withhold antimicrobials when the PCT was low. This is in stark contrast with the 86% compliance rate
with the recommendation to initiate antibiotics when the PCT was high.
7. Critically ill patients with signs and symptoms of infection should have a baseline PCT obtained for
trending purposes. A low PCT (or substantial decrease from baseline) during antibiotic treatment should
be used to shorten the duration of antimicrobial therapy. This could be accomplished through either
eliminating unnecessary antibiotics in patients who are not infectious or shortening the course of therapy
for patients who are infectious. This strategy has been proven safe and effective in a wide spectrum of
critically ill patients. Several studies have evaluated the utility of a PCT-guided strategy for determining
the appropriate time to discontinue and/or de-escalate antibiotics. These studies consistently show that
PCT guidance for discontinuing antimicrobial therapy led to decreases in antibiotic use without an
untoward outcome effect. This has been shown in various ICU populations, in patients with differing
severity of illness, and in those with proven infections.
8. Many different PCT guidance algorithms exist; Figure 2 represents a reasonable approach to using PCT
for antibiotic cessation.
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Patient with signs and symptoms of infection
Initiate appropriate empiric antimicrobial therapy and draw initial PCT
Day 3 of empiric ABX
Confirmed diagnosis of Overall, clinical suspicion for

Equivocal clinical suspicion
infection through clinical and infections is low, given clinical
of infection
microbiological criteria resolution and negative cultures
Draw PCT and use results to

Continue appropriate ABX,
guide therapy. If PCT suggests
de-escalate as appropriate, and
continuing empiric ABX, Stop empiric ABX
consider drawing serial PCT to
consider drawing serial PCT daily
determine therapy duration
to determine therapy duration
PCT < 0.25 mcg/L Decrease by ≥ 80% Decrease by < 80% Increase in PCT
from peak PCT, or from peak PCT, and compared with peak
PCT ≥ 0.25 and PCT ≥ 0.5 mcg/L concentration and
< 0.5 mcg/L PCT ≥ 0.5 mcg/L
Strongly encourage
Strongly encourage Encourage stopping Encourage continuing continuing or
stopping ABX ABX ABX escalating ABX
Figure 2. Sample procalcitonin-guided antimicrobial management algorithm.

ABX = antibiotics; PCT = procalcitonin.
Patient Case
4. A 64-year-old woman is admitted to the medical ICU with possible community-acquired pneumonia. The
patient is initiated on ceftriaxone and azithromycin. Chest radiography reveals focal infiltrate. On admission,
she is dyspneic with a respiratory rate of 33 breaths/minute. Her vital signs and laboratory values are as
follows: blood pressure 90/50 mm Hg, heart rate 101 beats/minute, WBC 18 x 103 cells/mm3, and lactate 4.2
mmol/L. A PCT is obtained on admission. The results are available 12 hours after antibiotics are initiated.
The PCT result is 0.1 mcg/L. Which is the most appropriate option, given the PCT result?
A. Continue all current antibiotics.
B. Discontinue all antibiotics.
C. Escalate antibiotics to piperacillin/tazobactam.
D. Discontinue ceftriaxone only.
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V. INTERPRETING SUSCEPTIBILITY REPORTS
A. Rationale: Identifying microorganisms and antibiotic susceptibilities is integral to the care of critically
ill patients with infections. An understanding of the microbiology laboratory methods for pathogen
identification and susceptibility testing will further equip critical care pharmacists with the ability to use the
most appropriate antimicrobial regimens for the treatment of critical care–associated infections. Standards
for antimicrobial identification, sensitivity testing, and determination of MIC breakpoints are determined by
the Clinical and Laboratory Standards Institute (CLSI). CLSI is a volunteer-driven standards development
organization that promotes the development and use of laboratory consensus standards and guidelines within
the health care community.
B. Methods for Antimicrobial Susceptibility Testing (AST)

1. Disk diffusion (Kirby-Bauer)
a. Test agar plates are swabbed with a standardized concentration of the test organisms; paper disks
containing a defined antibiotic concentration are then placed on the plates. The diameter of the zone
of inhibited growth is inversely proportional to the MIC value.
b. Usually reported qualitatively as sensitive, intermediate, or resistant
2. Dilution methods (i.e., broth dilution, agar dilution)
a. 2-fold serial dilutions of antibiotics are prepared (in either broth or agar), which are then inoculated
with a standardized concentration of test organisms.
b. The MIC is determined.
c. Precision of this method is within one 2-fold concentration in either direction.
d. Many prefabricated broth microdilution plates are commercially available.
3. E-test
a. A calibrated plastic strip with a range of continuous MIC values (with fifteen 2-fold dilutions) is
placed on an inoculated agar plate. The MIC can be determined by the intersection between the
zone of inhibition and the edge of the calibrated strip.
b. Complement other systems to determine the MIC for specific antibiotics and test for resistance and
for confirmatory testing
c. Studies have shown that the reading of the exact MIC on an E-test strip is subject to the user’s
interpretation and could lead to a one- or two-dilution error in either direction compared with
standardized methods.
4. Automated systems (e.g., Vitek, Microscan, Sensititre, Phoenix)
a. Uses computerized algorithms for interpreting MIC values
b. Can usually perform AST more quickly than traditional methods
c. More than 80% of all clinical microbiology laboratories report using an automated system as their
primary method of susceptibility testing.
d. May be unable to detect certain resistance mechanisms (i.e., inducible enzymes)
e. Standard inoculums of pathogens are used. For infections in which the in vivo inoculum may be
higher, certain antimicrobials may have higher MIC values.
5. Specific confirmatory tests for antimicrobial resistance
a. Macrolide-lincosamide-streptogramin resistance
i. Strains of Staphylococcus spp. can have a transferable resistance mechanism called macrolide-
lincosamide-streptogramin, which is inducible by clindamycin and can lead to treatment failure.
ii. Inducible resistance is not detected by routine AST.
iii. Detected using double-disk diffusion. See Figure 3 for an example of the double-disk diffusion
results.
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b. ESBL
i. CLSI procedures exist for K. pneumoniae, K. oxytoca, E. coli, and P. mirabilis.
ii. Initial screening with susceptibility testing for ceftazidime, aztreonam, cefotaxime, or
ceftriaxone
iii. Confirmatory testing with broth microdilution, disk diffusion, or E-test strips. See Figure 3 for
an example of the ESBL E-test confirmatory results. Presence of ESBL is confirmed if adding
clavulanic acid results in three 2-fold dilution decreases in the paired-cephalosporin MIC.
iv. Beginning in 2010, CLSI adopted lower MIC breakpoints for many cephalosporins for
Enterobacteriaceae (see Table 7). The rationale for this change is that the lower MIC may
more readily detect the presence of ESBL, hence eliminating the need for the labor-intensive
confirmatory tests. Compliance with this new practice is variable among clinical microbiology
laboratories. Clinicians should inquire within their local clinical microbiology laboratory
regarding whether the new standards have been adopted. If a microbiology laboratory has
adopted the new CLSI recommendations for ESBL detection, confirmatory tests be unnecessary.
Table 7. Changes to CLSI Enterobacteriaceae Breakpoints with 2010 Updates

Agent Pre-2010 CLSI Breakpoints 2010 CLSI Breakpoints
S I R S I R
Cefazolin ≤8 16 ≥ 32 ≤1 2 ≥4
Cefotaxime ≤8 16–32 ≥ 64 ≤1 2 ≥4
Ceftriaxone ≤8 16–32 ≥ 64 ≤1 2 ≥4
Ceftazidime ≤8 16 ≥ 32 ≤4 8 ≥ 16
Aztreonam ≤8 16 ≥ 32 ≤4 8 ≥ 16
c. AmpC β-Lactamase
i. Inhibitor-resistant β-lactamase (e.g., clavulanic acid, tazobactam)
ii. Maintains sensitivity with cephamycins (e.g., cefotetan, cefoxitin) and cloxacillin
iii. Confirmatory test with E-test containing cephamycin alone or a combination of cephamycin
and cloxacillin. If the MIC is decreased by more than three 2-fold dilutions, the presence of
AmpC β-lactamase is confirmed.
d. Carbapenemase
i. Metallo-β-lactamase (e.g., New Delhi metallo-β-lactamase [NDM]; Verona integrin-encoded
metallo-β-lactamase [VIM]); IMP-type carbapenemase)
(a) Hydrolyzes both β-lactam and carbapenem antibiotics, but aztreonam maintains
susceptibility. Clinically, about 80% of metallo-β-lactamase–containing pathogens are
resistant to aztreonam because of other resistance mechanisms.
(b) Zinc-mediated metallo β lactamase can be repressed by ethylene-diamine tetraacetic acid
(EDTA). Reduction in imipenem MIC by more than three 2-fold dilutions in the presence
of EDTA confirms presence of zinc mediated metallo β-lactamase.
ii. KPC
(a) KPC enzyme can produce a slightly higher MIC that may still be in the range considered
sensitive. This is in contrast to other carbapenem-resistant mechanisms in Pseudomonas
and Acinetobacter, which generally produce a fully resistant MIC. Hence, a carbapenem
MIC of 1 mcg/mL or greater in an Enterobacteriaceae should be evaluated through further
confirmatory testing.
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(b) Modified Hodge test should be performed for pathogens with an elevated carbapenem
MIC. See Figure 3 for an example of the modified Hodge test result.
(1) Plate standard sensitive E. coli strain on entire plate.
(2) Place meropenem or carbapenem disk in center of test area.
(3) Streak test organism in a straight line from edge of carbapenem disk to edge of plate
(up to four different organisms can be tested).
(4) Positive carbapenemase results from modified Hodge test have a clover leaf–like
indentation of the E. coli growing along the test organism’s streak.
(c) Starting in 2010, CLSI lowered the susceptibility breakpoints for carbapenem (0.5 mcg/mL
and 1.0 mcg/mL or less for ertapenem and other carbapenems, respectively), with the intent
of eliminating the need for confirmatory tests.
(1) Clinicians should inquire about the practices of their local microbiology laboratory
regarding carbapenem susceptibility.
(2) Particularly when confirmatory tests are not being performed, and a laboratory
continues to use the older MIC breakpoints, a higher clinical suspicion for
carbapenemase is warranted.
(3) Ertapenem resistance seen on AST is a sensitive marker for the presence of
carbapenemase. Before the 2010 reclassification of carbapenem susceptibility
breakpoints, there were reports of up to 46% of clinical isolates with genotypic evidence
of KPC-producing enzymes being inadvertently labeled as imipenem sensitive.
(4) Deleterious outcomes associated with the use of carbapenems in carbapenemase-
producing organisms have been reported.
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A. B.
C.
Figure 3. Sample microbiology confirmatory tests for specific resistance mechanisms.

(A) Positive double-disk diffusion test (D-test) shows the induction of clindamycin resistance by erythromycin. This is indicated by a flattening of the zone
in the area between the disks where both drugs have diffused.
(B) Confirmatory tests for ESBL with the use of an E-test. The strip on the left contains cefotaxime plus clavulanic acid (CTL) and cefotaxime alone (CT).
The strip on the right contains ceftazidime plus clavulanic acid (TZL) and ceftazidime alone (TZ). ESBL confirmation can be determined by the distortion of
the cefotaxime eclipse. It could also be confirmed by three or more 2-fold dilution decreases in MIC with the addition of clavulanic acid.
(C) Streaks 1 and 3 represent positive modified Hodge test results, and streak 2 represents a negative result.
Reproduced with permission from: Kuper KM, Boles DM, Mohr JF, et al. Antimicrobial susceptibility testing: a primer for clinicians. Pharmacotherapy
2009;29:1326-43.
C. MIC Breakpoints: Determining the correct MIC breakpoint by the governing standards is a complicated
process. CLSI promotes the development of voluntary consensus standards within the medical community.
Determining CLSI breakpoints could be based on several conflicting interests, which may include some of
the following:
1. Microbiological: MIC that distinguishes wild-type bacteria from those that have acquired additional
resistance mechanisms
2. PK/PD: Derived from human or animal data and modeled to determine the likelihood that standard
prescribed doses will meet specified PD criteria for suppressing bacterial growth
3. Breakpoints that may decrease the need for confirmatory tests, hence decreasing the microbiology
laboratory workload. Such an approach, although possibly sensitive for determining the presence of
resistance mechanisms, may potentially lead to the compensatory use of broader antimicrobials.
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4. The CLSI breakpoints may be inconsistent with the breakpoints established by the FDA. Automated
systems report MIC breakpoints according to FDA approvals. Changes to reporting and labeling require
additional clearance from the FDA. Unfortunately, the FDA labeling may not be up to date with the
current CLSI recommendations. Hence, despite newer CLSI recommendations, many institutions may
still be reporting susceptibility results that are based on their respective FDA labeling breakpoints.
These breakpoints may result in pathogens being labeled as sensitive, even though, according to the
current CLSI standards, they would be considered resistant.
5. The exact MIC breakpoints that are used by a local microbiology laboratory can be variable, depending
on the laboratory’s adaptation of new standards. In addition, there are significant variations in the FDA-
approved breakpoints used by automated AST methods and updated CLSI guidelines. Once again, this
highlights the importance of a clinician’s understanding of the exact methods and breakpoints that are
used in his or her institution.
D. Minimum Information That Each Critical Care Pharmacist Should Know About His or Her Local
Microbiology Laboratory Practices
1. Routine methods for AST
2. Availability of rapid diagnostic tests for speciation or resistance gene identification
3. If additional tests are available (E-test, genotyping, etc.) and how to go about requesting additional
information
4. Are confirmatory tests for resistance mechanisms routinely done (e.g., double-disk diffusion for
macrolide-lincosamide-streptogramin–inducible resistance, ESBL and KPC confirmatory tests)?
5. What is the usual procedure for censoring the AST results?
a. Does the AST result try to guide clinical decision (i.e., if pathogen were sensitive to oxacillin, would
vancomycin results be censored)?
b. If certain resistance mechanisms are detected, would the laboratory automatically update
susceptibility results (i.e., if ESBL were detected, would β-lactam/β-lactamase combination
antibiotics automatically be changed to resistant)?
c. Are any antibiotics part of the standard panel, but routinely hidden from clinical reports?
d. Most microbiology laboratories would retain all the information, even if parts of the results had
been censored. Critical care pharmacists should consider contacting the microbiology laboratories
to see whether additional information regarding the pathogen is available.
6. When an MIC is reported, is only the MIC breakpoint reported (i.e., MIC 2 mcg/mL or less), or is the
actual MIC reported (i.e., 0.25 mcg/mL)?
7. Are the breakpoints reported consistent with the updated CLSI recommendations?
E. Clinical Application of Interpreting AST

1. The ideal application of AST interpretation and clinical therapeutics may include the following:
a. Knowledge of the individual pathogen and the corresponding MIC breakpoints for each of the tested
antibiotics
b. Potential reasoning behind each of the clinical breakpoint designations (i.e., wild-type selection,
PK/PD breakpoints assessment, screening for resistance)
c. Accurate comprehension of the local AST methods used and potential limitations of the MIC
reported
d. Understanding of the tested antimicrobial’s PD parameters, which conveys the highest likelihood
for eradication of the microorganism
e. Selecting the most appropriate antibiotic according to an assessment of the following:
i. What genotypic resistance mechanisms may be suggested by the phenotypic representation of
the AST?
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ii. How may the underlying resistance mechanisms affect the choice of antimicrobial therapy?
iii. The PK characteristics of the medication and patient characteristics that may affect the
antimicrobial’s PK
iv. The likelihood that the considered antimicrobial agent will reach its PD targets for optimal
therapy at the local site of infection
v. Selecting the antimicrobial according to a balance of antimicrobial stewardship principles,
adverse effects profile, allergies, and cost
2. AST interpretation and selection of the optimal antibiotic is a small part of determining a patient’s
clinical course. Studies have mainly shown that the therapeutic outcome in infections when treated
with antibiotics deemed susceptible by AST is around 90%, whereas the response to antibiotics deemed
resistant is about 60%. This could partly explain why many clinical studies evaluating the optimization
of PK/PD parameters have equivocal findings. However, although clinical studies have conflicting results
regarding the utility of AST interpretation and optimization of PK/PD, the biologic plausibility of this
approach will probably allow the best opportunity of recovery for each patient.
3. When an antimicrobial must be chosen despite its having a higher-than-ideal MIC, the penetration into
the site of infection is questionable, or the correlation of PK and PD target attainment is not available,
additional interventions may be required. Optimization of therapy should be tried through one or more
of the following: using a higher dose, using administration strategies that may optimize PK/PD (i.e.,
extended- or continuous-infusion β-lactams), or combination therapy.
VI. MECHANISMS OF ANTIBACTERIAL RESISTANCE AND TREATMENT OF MULTIDRUG-

RESISTANT PATHOGENS
A. Epidemiology and Clinical Significance: The World Health Organization has identified antimicrobial
resistance as one of the three greatest threats to human health.
1. The National Healthcare Safety Network for the CDC reports recent resistance rates among commonly
encountered pathogens. More than 2000 U.S. hospitals participate in this national surveillance program,
with more than 80,000 pathogens reported and about 70% of the reporting from critical care sites. See
Table 8 for selected resistance rates in different hospital-acquired infections.
2. Resistance rates continue to be high, with trends toward an increase in certain pathogens compared with
the reports from previous years.
3. Resistant pathogens consistently correlate with worse clinical outcomes, which may partly be explained
by the higher likelihood of empiric treatment with a resistant antibiotic.
4. The antibiotic pipeline has slowed down considerably, with consistent decreases in FDA approvals of
antimicrobial agents during the past 3 decades. The combination of prevailing resistance, including the
emergence of pan-resistant pathogens, with the lack of new antimicrobial agents presents a potential
global health problem.
5. An understanding of resistance mechanisms would assist the ICU clinician in effectively treating
current resistant pathogens while incorporating antimicrobial stewardship principles to prevent further
resistance. See Table 9 for common mechanisms of resistance.
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Table 8. Recent Resistance Rates in Hospital-Acquired Infection (2009–2010)

CLABSI % CAUTI % VAP % SSI %
Pathogen (total n) Resistance Resistance Resistance Resistance
Gram-negative Bacteria
E. coli (9351)
Third-generation cephalosporins 19.0 12.3 16.3 10.9
Carbapenem 1.9 2.3 3.5 2.0
Fluoroquinolone 41.8 31.2 35.2 25.3
Multidrug resistanta 3.7 2.0 3.3 1.6
K. pneumoniae/oxytoca (6470)
Carbapenem 12.8 12.5 13.4 7.9
P. aeruginosa (6111)
Aminoglycosides 10.0 10.9 11.3 6.0
Ceftazidime or cefepime 26.1 25.2 28.4 10.2
Fluoroquinolones 30.5 33.5 32.7 16.9
Carbapenem 26.1 21.3 30.2 11.0
Piperacillin/tazobactam 17.4 16.6 19.7 6.8
Enterobacter spp.(3821)
Carbapenem 4.0 4.6 3.6 2.4
A. baumannii (1490)
Carbapenem 62.6 74.2 61.2 37.3
Multidrug resistant 67.6 77.6 63.4 43.9
Gram-positive Bacteria
S. aureus (12,635)
Oxacillin 54.6 58.7 48.4 43.7
E. faecalis (5484)
Vancomycin 82.6 82.5 82.6 62.3
E. faecium (3314)
Vancomycin 9.5 8.4 9.8 6.2
a
Multidrug resistant is defined as being either intermediate or resistant to at least one drug in three of the following five classes: third- and fourth-generation
cephalosporins, fluoroquinolones, aminoglycosides, carbapenems, and piperacillin and/or piperacillin/tazobactam.
CAUTI = catheter-associated urinary tract infection; CLABSI = central line–associated bloodstream infection; SSI = surgical site infection; VAP = ventilator-
associated pneumonia.
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Table 9. Common Resistance Mechanisms

Antibacterial Agent Mechanism of Resistance
β-Lactamases (AmpC, ESBL, KPC)
Reduced permeability
β-Lactams
Altered penicillin binding proteins
Increased efflux
Altered DNA gyrase and topoisomerase
Fluoroquinolones Increased efflux
Decreased protein targets
Increased efflux
Macrolides
Methylating enzymes
Aminoglycoside-modifying enzymes
Aminoglycosides Increased efflux
Modification of target proteins
Altered target
Glycopeptides
Decreased permeability
Increased efflux
Tetracyclines
Protection of target proteins
Increased efflux
Trimethoprim
Altered dehydrocholate reductase
Rifamycin Altered RNA polymerase
B. Mechanisms of Resistance (bacteria often possess several mechanisms)

1. Decreased permeability (i.e., porin loss, thickened cell wall)
2. Increased efflux (i.e., macrolide efflux pump)
3. Target modification (i.e., alteration in penicillin-binding proteins)
4. Hydrolysis (i.e., β-lactamases, aminoglycoside-modifying enzymes)
C. Factors Associated with Resistance Acquisition

1. Crowding of patients with high levels of disease acuity and/or antimicrobial use
2. Prolonged hospital LOS
3. Colonization pressure: Proportions of people colonized with resistant bacteria. Combated by strict
compliance with infection control procedures to prevent colonization, adequate nurse staffing ratios, and
hand hygiene
4. Use of invasive devices (endotracheal tubes, intravascular catheters, and urinary catheters)
5. Previous use of antibiotics
D. Clinical Approach to Common Pathogen Resistance Seen in Critically Ill Patients

1. ESBL
a. Confers resistance to third-generation cephalosporins and aztreonam
b. Found primarily in E. coli and K. pneumoniae spp., but can also be seen in other Enterobacteriaceae
c. Carbapenems should be considered the drug of choice in severe infections.
d. Non–β-lactams could be used if they showed sensitivity on AST; however, because ESBLs are
usually plasmid mediated, there are often other acquired resistance mechanisms. The rates of cross-
resistance to other classes of antibiotics are 55%–100%.
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e. β-Lactams/β-lactamase inhibitors and cefepime often have in vitro activity, though clinical failures
have been reported.
i. Several early reports showed that carbapenems, compared with non-carbapenems, result
in improvements in clinical and microbiological outcomes. These studies were usually
observational and contained relatively few patients. This led to several expert recommendations
to use carbapenems exclusively for the treatment of ESBL infections. Furthermore, although
never endorsed by CLSI, many microbiology laboratories decided to censor all β-lactam/β-
lactamase inhibitor AST results to show resistance if ESBL was detected. Hence, controlled
studies of β-lactam/β-lactamase inhibitors or cefepime versus carbapenem were never
performed.
ii. A recent study performed a post hoc analysis of six prospective cohort studies and compared
the use of β-lactam/β-lactamase inhibitors with carbapenems for the empiric and definitive
treatment of ESBL-producing E. coli bacteremia. Neither univariate nor multivariate analysis
showed that β-lactam/β-lactamase inhibitor use was associated with worsening mortality or
hospital LOS. Two important caveats came from this study. Of note, the sickest patients in this
study were treated with carbapenems. In addition, in most patients, either the urinary or the
biliary tract was the source of the bacteremia. Finally, the study routinely used the maximum
dose of piperacillin/tazobactam (4.5 g every 6 hours). Taken together, this would suggest that
using high-dose β-lactam/β-lactamase inhibitors to treat ESBL should be reserved for relatively
stable patients, with a source of infection with relatively low inoculums.
iii. A subsequent study showed that the piperacillin/tazobactam MIC was significantly correlated
with outcomes in patients with ESBL bacteremia. All patients with a urinary source of
bacteremia survived regardless of the piperacillin/tazobactam MIC as long as it was within the
sensitive breakpoint. However, in non–urinary tract sources of bacteremia, an MIC greater than
2 mcg/mL was associated with worse outcomes.
iv. Data are conflicting regarding the use of cefepime for treating ESBL infections. Some studies
show worse outcomes, whereas others show no difference compared with carbapenems. This
may partly be explained by the cefepime MIC distribution. Traditionally (before 2014), the
sensitive breakpoint for cefepime for Enterobacteriaceae was 8 mcg/mL or less. However, in
2014, CLSI recommended decreasing the sensitive cefepime MIC breakpoint to 2 mcg/mL, in
addition to a new category for sensitive-dose dependent, where maximal doses of cefepime are
recommended for MICs of 4 and 8 mcg/mL. Hence, for many years, cefepime may have been
used in ESBL infections when the MIC was 4–8 mcg/mL, but doses were not optimized.
v. Of interest, a recent investigation correlated cefepime MIC to ESBL Enterobacteriaceae with
mortality, where a cefepime MIC of 1 mcg/mL or less was associated significantly lower
mortality compared with other MIC values. Together, given the conflicting clinical results, it
is difficult to endorse the use of cefepime for the treatment of ESBL infections. However, in a
stable patient with an ESBL infection having a cefepime MIC of 1 mcg/mL or less, cefepime
may be considered for consolidative therapy in an attempt to minimize carbapenem use.
2. AmpC β-lactamases
a. Confer resistance to penicillins and narrow-spectrum cephalosporins
b. β-Lactamase inhibitor resistant; hence, tazobactam and clavulanic acid would not provide additional
coverage
c. Innate low-level production in many gram-negative bacteria (i.e., Enterobacter, Citrobacter, Serratia,
Morganella, Providencia, and Pseudomonas). This low-level production leads to resistance against
penicillin, ampicillin, and first-generation cephalosporins.
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d. Genetic mutation leading to sustained high-level production is possible (de-repressed mutants).

i. Theoretically, treatment with third-generation cephalosporins or broad-spectrum cephalosporins
for non–de-repressed mutants may select species with the mutation. The actual incidence of
breakthrough infections is unknown with de-repressed mutants when bacteria with innate
AmpC β-lactamase production are treated with third-generation cephalosporins or extended-
spectrum penicillins. However, it is believed to be low.
ii. Several epidemiologic studies have linked the use of third-generation cephalosporins with the
increase in pathogenic species of AmpC hyperproducing Enterobacteriaceae.
iii. De-repression confers resistance to third-generation cephalosporins and broad-spectrum
penicillins (piperacillin, ticarcillin).
iv. Commonly occurs in E. cloacae and Citrobacter freundii
v. Cefepime generally retains activity against de-repressed mutants.
vi. Carbapenem and cefepime should be considered the drugs of choice in severe infections.
vii. Because de-repression results from the mutation of a chromosomal-mediated β-lactamase,
not from plasmids, many hyperproducers of AmpC retain activity against other non β-lactam
antimicrobials (e.g., fluoroquinolones, aminoglycosides).
Patient Case
5. A 74-year-old man is admitted to the surgical ICU after elective hip replacement surgery. The patient, who
has a history of chronic pulmonary obstructive disease, cannot be weaned off the ventilator after surgery.
During the patient’s course, he develops signs and symptoms of infection. His vital signs and laboratory
values are as follows: blood pressure 94/55 mm Hg, heart rate 114 beats/minute, temperature 101.9°F, WBC
18 x 103 cells/mm3, and lactate 3.2 mmol/L. The patient is empirically initiated on piperacillin/tazobactam
and vancomycin and given 2 L of crystalloid fluids; pan cultures are sent. Urinalysis reveals pyuria, positive
leukocyte esterases, and nitrites. Blood and sputum cultures are negative, but urine culture shows E. coli.
The patient’s urinary catheter is removed, and vancomycin is discontinued. On day 3 of therapy, antibiotic
susceptibility results are available. The patient’s E. coli is resistant to third-generation cephalosporins with
laboratory confirmation of the presence of ESBL. The laboratory reports the following antimicrobials and
corresponding MIC values: piperacillin/tazobactam less than 2 mcg/mL – S; cefepime 4 mcg/mL – S;
imipenem 0.5 mcg/mL – S; and ciprofloxacin 1 mcg/mL – S. The patient’s vital signs and laboratory values
are as follows: blood pressure 110/70 mm Hg, heart rate 98 beats/minute, respiratory rate 30 breaths/minute,
temperature 98.7°F, and WBC 9 x 103 cells/mm3. Which is the most appropriate antibiotic option?
A. Change piperacillin/tazobactam to imipenem.
B. Continue piperacillin/tazobactam alone.
C. Change piperacillin/tazobactam to cefepime.
D. Add ciprofloxacin to piperacillin/tazobactam.
3. Carbapenemase
a. Seen in Acinetobacter, Pseudomonas, and Enterobacteriaceae
b. The global spread of carbapenem resistance has become an epidemic.
c. The CDC recently reported that carbapenem-resistant Enterobacteriaceae (CRE) is an urgent hazard
level, where high consequence and probability for widespread public health concerns exist.
d. Confers resistance to most β-lactams, including carbapenems, cephalosporins, monobactam, and
broad-spectrum penicillins
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e. Treatment options
i. Tigecycline:
(a) Glycylcycline antibiotic, which is structurally similar to tetracyclines
(b) Mechanism of action: Inhibition of 30s ribosomal subunit
(c) Spectrum of activity:
(1) Gram-positive bacteria: Enterococcus (including vancomycin-resistant enterococci),
Listeria, Staphylococcus (including MRSA/CoNS), Streptococcus
(2) Most gram-negative bacteria, including Acinetobacter, ESBL-producing Enterobacte-
riaceae, de-repressed AmpC Enterobacteriaceae, CRE, and Stenotrophomonas
(3) Anaerobes, including Bacteroides and Clostridium
(4) Atypicals
(5) Does not cover Pseudomonas, Providencia, or Proteus
(d) PK
(1) Wide volume of distribution: 7–10 L/kg
(2) The intracellular distribution of tigecycline results in a decreased serum/tissue
concentration ratio. This has led many clinicians to state that tigecycline is not the
ideal drug for bloodstream infections. However, tigecycline has not been evaluated
exclusively for the treatment of bloodstream infections. In a pooled analysis of eight
studies, patients with secondary bacteremia treated with tigecycline were compared
with patients treated with other antibiotics. Overall, no significant differences in
outcomes were seen. Despite these results, clinicians should exert caution with the use
of tigecycline for bacteremia and should reserve tigecycline for pathogens when no
other antibiotics are viable options.
(3) Primarily biliary elimination
(4) Urinary elimination is 8%–11%. The low urinary elimination may limit tigecycline’s
role in treating UTIs. The use of tigecycline for treating multidrug-resistant UTIs
has been reported only in case reports, with most reports showing treatment success.
However, a recent evaluation of tigecycline for the treatment of KPC bacteriuria
indicated a correlation with the subsequent development of tigecycline resistance.
Without further data, tigecycline should not routinely be used for UTIs when other
treatment options are available.
(5) Poor penetration into lung epithelial lining fluid, which is in contrast to high penetration
into lung alveolar cells. This characteristic may partly explain the findings of a study
evaluating tigecycline compared with imipenem for the treatment of hospital-acquired
pneumonia. This study showed that tigecycline had a lower treatment success rate
than imipenem. The difference in treatment success was mainly attributable to the
significant differences in patients with ventilator-associated pneumonia. There was
also a trend toward increased mortality in the subgroup of patients with ventilator-
associated pneumonia.
(e) The FDA issued a safety warning in 2010 indicating a possible increased mortality risk
associated with the use of the tigecycline compared with other drugs used to treat a variety
of other serious infections. This was compiled using several phase III studies in which
tigecycline had been proven noninferior to other standard treatments. Subsequently,
several other meta-analyses were published with conflicting results regarding tigecycline’s
increased mortality risk.
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(f) Given tigecycline’s possible shortcomings, it seems prudent to avoid the routine use of
tigecycline in infections when other treatment options are available. However, tigecycline
may be one of the few remaining antibiotic options for treating carbapenem-resistant
pathogens. When tigecycline must be used because of limited treatment options, clinicians
should consider administering combination therapy.
(g) Resistance to tigecycline has been reported. Clinicians should seek confirmation from their
microbiology laboratory regarding tigecycline sensitivity. Of note, CLSI currently has no
recommendation for MIC breakpoint for tigecycline against Acinetobacter spp. The MIC
breakpoint for sensitivity against Enterobacteriaceae is 2 mcg/mL or less.
ii. Polymyxins:
(a) Colistin (polymyxin E)
(1) Mechanism of action: A cationic cyclic decapeptide that functions by displacing calcium
and magnesium from the outer cell membrane, hence changing the permeability of the
cell membrane to allow insertion of the molecule into the cell membrane. Once the
molecule is inserted into the cell membrane, it disrupts the cell membrane integrity
and subsequently leads to cell death.
(2) Spectrum of activity: Covers only gram-negative bacteria, including CRE. Does not
cover Proteus, Providencia, Burkholderia, Serratia, or Stenotrophomonas
(3) First used in the United States in the 1960s, but fell out of favor because of reports of
nephrotoxicity and neurotoxicity
(4) Around 2000, with the emergence of CRE, colistin use was reconsidered, given the
lack of treatment options.
(5) Dosing challenges
(A) Different products provide different dosing recommendations.
(B) Colomycin injection is the brand primarily used in Europe. Dosed in international
units (IU)
(C) Coly-Mycin is the brand primarily used in the United States. Dosing in colistin-
based activity
(D) 3 million IU of colistin is equal to about 100 mg of colistin-based activity.
(6) PK/PD
(A) All colistin products, regardless of the dosing units, are administered as
colistimethate, which is a prodrug. Colistimethate is hydrolyzed to the active drug
colistin.
(B) Colistimethate is excreted through renal clearance, whereas the active drug
colistin is cleared by non-renal pathways. Hence, renal dysfunction leads to a
higher portion of colistimethate being present for hydrolysis into colistin, thus
increasing the final active drug concentration.
(C) PD parameter for maximal activity is area under the curve/MIC ratio.
(D) In the 1960s, the dosing recommendations and PK/PD parameters were largely
unknown because the methods for evaluations were drastically different from the
current standards.
(E) Recent PK/PD evaluations show that traditional dosing methods are probably
insufficient to reach adequate serum concentrations to maximize PD target
attainment.
(F) Several studies have reported that a higher colistin dose is associated with
significant improvements in clinical outcomes.
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(G) The exact dosing regimen to be used has not been elucidated. However, one group of
investigators, using PK modeling, proposed the following dosing recommendations:
• All dosing with ideal body weight
• All CrCl values calculated by the Jeliffe equation
• Usual colistin concentration target: 2.5 mcg/mL
• Loading dose: Colistin target x 2.0 x ideal body weight
• Maintenance dose:
• Not on renal replacement therapy: Daily dose = colistin target x (1.5 x CrCl
+ 30) divided every 8–12 hours
• On intermittent dialysis: Daily dose of colistin on non-dialysis days = colis-
tin target x 30
• On continuous dialysis: Daily dose = colistin target x 192 divided every
8–12 hours
(H) Several ongoing investigations are evaluating the effects of high-dose colistin
regimens and the utility of using a loading dose.
• One study from South America is recruiting patients to evaluate the utility of a
200-mg loading dose.
• One study reported a 300-mg loading dose regimen, followed by 150 mg
every 12 hours. This study was non-comparative, but it reported high rates of
clinical success.
(7) Because the PK/PD of colistin is unclear and little is known regarding the optimal
dosing regimen, colistin should be reserved for infections in which other treatment
options are not available. In such cases, it may be prudent to administer combination
therapy. Furthermore, many in vitro studies have shown synergy between colistin and
other antimicrobials.
(8) Resistance to colistin has been reported. In vitro studies also show that colistin
resistance develops quickly, which may be another rationale for providing combination
therapy. Clinicians should verify colistin susceptibility with their local microbiology
laboratory.
(A) Routine monitoring of colistin concentrations is currently infeasible.
(B) According to PK data, an MIC of 2 mcg/mL or less should be considered sensitive.
(b) Adverse reaction: Nephrotoxicity
(1) Nephrotoxicity
(A) 0%–45% reported in recent literature, depending on the definitions used for renal
dysfunction
(B) In general, seems to be dose-dependent
(C) Usually reversible, with few cases leading to a prolonged need for renal replacement
therapy
(2) Neurotoxicity
(A) Ranging from paresthesia to apnea
(B) Incidence of 8%–27% reported in historical studies
(C) Mentioned only in case reports in the current era of colistin use
(c) Polymyxin B:
(1) Mechanism of action, spectrum of activity, and adverse reactions similar to those of
colistin
(2) Available in the United States, but not in Europe and Australia
(A) PK/PD
(B) Administered as an active drug
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(C) PD targets similar to those of colistin

• Similar unknowns regarding best dosing regimen to achieve PD parameters
• Manufacturer-recommended dosing: 1.5–2.5 mg/kg/day divided every 12
hours. Recommends renal dose adjustment, but recent studies suggest minimal
renal clearance
iii. Ceftazidime/avibactam
(a) Avibactam is a new β-lactamase inhibitor recently approved by the FDA.
(b) Spectrum of activity: Broad gram-negative activity, including multidrug-resistant
Pseudomonas and Enterobacteriaceae. Adding avibactam allows coverage against KPC-
producing bacteria, together with coverage against other β-lactamases (OXA, CTX-M,
AmpC). Minimal coverage against Acinetobacter spp., gram-positive, and anaerobes
(c) FDA approved for the treatment of complicated intra-abdominal infection and complex
UTIs. However, most clinicians will reserve its coverage for difficult-to-treat pathogens
with minimal coverage options, such as KPC-producing Enterobacteriaceae.
(d) An in vitro study that included 120 KPC-producing pathogens showed good activity with
ceftazidime/avibactam.
(e) No major adverse effects were seen with ceftazidime/avibactam in phase II and phase III
studies.
(f) Currently, the average wholesale price for ceftazidime/avibactam is about $900 per day
with normal dosing.
iv. Combination therapy
(a) Several retrospective studies suggested that the use of combination therapy is warranted
for the treatment of CRE, particularly a regimen involving colistin, tigecycline, and a
carbapenem. Interpreting these studies is difficult. Many were non-interventional, hence
leading to the evaluation of many treatment regimens. The increased ratio of the number
of treatment regimens to the number of patients substantially increases the risk of spurious
findings. If no optimal therapy exists for a patient, combination therapy may be considered.
These therapies include scenarios in which the carbapenem MIC may be slightly elevated
or in which therapies with suboptimal PK/PD (i.e., colistin and tigecycline) are used.
(b) A recent retrospective study that evaluated the role of combination therapy for carbapenem-
resistant gram-negative pathogens showed that combination therapy with several agents, all
of which had in vitro sensitivity, led to improvements in outcomes. In contrast, combination
therapy with several agents, not all of which had in vitro sensitivity, did not lead to
improvements.
(c) Several case reports recommend considering combining ertapenem with another
carbapenem for the treatment of carbapenem-resistant pathogens. This approach takes
advantage of the increased affinity for ertapenem seen in vitro with carbapenemases. Hence,
administering ertapenem as a sacrificial carbapenem may allow a different carbapenem to
exert its effects. However, this practice requires further testing; hence, it cannot currently
be recommended.
4. Multidrug-resistant Pseudomonas
a. Resistance mechanisms seen with P. aeruginosa are unpredictable. The presence of several
mechanisms, including β-lactamases, porin-loss, efflux pump, and alteration of target proteins,
complicates treatment options.
b. Clinical approach usually entails empiric coverage with a β-lactam, which has the best local in vitro
activity against Pseudomonas, with or without a second antipseudomonal agent. Therapy could be
de-escalated to a monotherapy with the narrowest spectrum on availability of AST results.
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c. Ceftolozane/tazobactam is a novel β-lactam/β-lactamase inhibitor antimicrobial with enhanced

activity against P. aeruginosa.
i. Ceftolozane is a novel third-generation cephalosporin.
ii. Spectrum of activity: Gram-negative organisms, including P. aeruginosa. Activity includes
coverage against ESBL and AMP-C β-lactamase–producing organisms. Limited gram-positive
and anaerobic coverage. Among multidrug-resistant and extended drug–resistant Pseudomonas,
ceftolozane/tazobactam retains good activity, with its MIC of 90 mcg/mL still below the MIC
breakpoint for resistant, as determined by the FDA.
iii. FDA approved for the treatment of complicated intra-abdominal infection and complicated
UTI. However, clinically, its coverage will most likely be reserved for resistant pseudomonal
infections.
5. MRSA
a. MRSA is a significant cause of both community- and hospital-acquired infection.
b. Skin and soft tissue infections
i. Community-acquired MRSA often presents as a skin and soft tissue infection.
ii. Cutaneous infections and abscesses are best treated with adequate drainage.
iii. Antibiotics are usually not necessary unless the patient does not respond to drainage, has
extensive disease, or has signs and symptoms of systemic infection.
iv. Antibiotic treatment choices for mild community-acquired MRSA cutaneous and skin infections
include trimethoprim/sulfamethoxazole, clindamycin, and tetracycline.
c. MRSA bacteremia and endocarditis
i. Can be treated with either vancomycin or daptomycin
ii. In a study of patients with right-sided endocarditis, daptomycin was noninferior to vancomycin.
Of interest, treatment response was poor with both therapies, with only about 40% in each
group meeting that outcome. Daptomycin was dosed at 6 mg/kg in this study.
iii. Some experts recommend giving higher daptomycin doses (8–10 mg/kg) to optimize the
PD target attainment for daptomycin. However, this approach requires further investigation.
Daptomycin resistance in S. aureus has been reported. A correlation appears to exist between
intermediate sensitivity to vancomycin, thought to be caused by a thickened cell wall–limiting
penetration, and decreased susceptibility to daptomycin. Currently, the daptomycin MIC for
MRSA is 1 mcg/mL or less.
iv. Several investigations have also evaluated daptomycin compared with vancomycin for
MRSA bacteremia when the vancomycin MIC was greater than 1 mcg/mL. Although these
investigations showed outcome benefit associated with daptomycin use, the studies have severe
limitations, which may limit their applicability.
(a) Retrospective analyses
(b) Daptomycin was usually used as definitive therapy after an initial course of vancomycin.
(c) Daptomycin use in one study was associated with a significantly higher rate of infectious
diseases consultation, which may have other treatment implications.
(d) Given study limitations, the routine use of daptomycin for MRSA infections when the
vancomycin MIC is greater than 1 mcg/mL cannot be recommended.
(e) The 2011 IDSA guidelines for the treatment of MRSA state that the treatment of isolates
with a vancomycin MIC of 2 mcg/mL or less should be determined by the patient’s response
to vancomycin, independent of the MIC.
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d. MRSA pneumonia. Community-acquired MRSA pneumonia can be treated with either vancomycin
or linezolid. Clindamycin can be considered if the strain is susceptible.
i. Community-acquired MRSA infections may be associated with the presence of Panton-
Valentine leukocidin, which is a two-component staphylococcal membrane toxin that targets
leukocytes. This toxin has been linked with severe infections, necrotizing pneumonia, and
abscess formation. Theoretically, clindamycin and linezolid, being ribosomal subunit and
protein synthesis inhibitors, may attenuate the amount of toxin production.
ii. A recent randomized controlled study included patients with hospital-acquired pneumonia,
health care–associated pneumonia, and ventilator-associated pneumonia who have a baseline
respiratory culture positive for MRSA.
(a) Vancomycin was dosed by weight and adjusted locally according to trough levels.
(b) This was a noninferiority study with nested superiority criteria where the primary end
point was clinical response at the end of the study.
(c) Clinical response was defined as resolution of signs of pneumonia with no further need for
other antibiotics.
(d) Study met both the noninferiority and the superiority criteria with respect to clinical
response and microbiological clearance.
(e) Study may have been confounded by less than 50% of patients reaching vancomycin
target concentrations by day 3 and the vancomycin patients having a slightly higher rate of
baseline bacteremia.
(f) No difference in mortality was seen.
(g) Many clinicians interpret the results from this study as suggesting that either vancomycin
or linezolid can be considered for the treatment of MRSA pneumonia.
e. Novel agents for the treatment of MRSA
i. Dalbavancin and oritavancin recently received FDA approval for the treatment of skin and soft
tissue infections.
(a) Antimicrobial class: Lipoglycopeptide
(b) Spectrum of activity: Gram-positive pathogens including MRSA, vancomycin-resistant
enterococci, vancomycin-resistant staphylococci, and drug-resistant S. pneumoniae
(c) PK and dosing: High protein binding and long half-life allow for extended-interval dosing.
(1) Dalbavancin is administered as a 1000-mg dose, followed by 500 mg 1 week later. In
patients with a CrCl less than 30 mL/minute/1.73 m2, the dose is reduced to 750 mg
once, followed by 375 mg 1 week later. No dosage adjustments are needed if patients
are on scheduled intermittent hemodialysis.
(2) Oritavancin was evaluated as a 1200-mg one-time dose. No dosage adjustments are
needed for patients with mild to moderate renal dysfunction; however, it has not been
evaluated in patients on scheduled intermittent dialysis.
(d) Studies
(1) In a noninferiority study, once-weekly dalbavancin was noninferior to twice-daily
vancomycin followed by oral linezolid for the treatment of skin and soft tissue
infections. In addition, fewer adverse drug effects occurred in the dalbavancin group.
(2) In a noninferiority study, an oritavancin one-time dose was found to be noninferior
to twice-daily vancomycin for the treatment of skin and soft tissue infections. Similar
rates of adverse effects were seen.
(3) Both studies were well designed, and each conformed to the FDA guidelines for the
conduct of a noninferiority study for skin and soft tissue infections. However, long-
acting antimicrobials pose additional challenges in hospitalized patients, including
ensuring appropriate physician follow-up, reimbursements for inpatient administration,
and ways to handle adverse drug reactions.
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(e) Application. Place in therapy among critically ill patients is limited. May be suitable for
critically ill patients transitioning to a long-term acute care facility
ii. Tedizolid recently received FDA approval for the treatment of bacterial skin and skin structure
infection.
(a) Antimicrobial class: Oxazolidinone
(b) Spectrum of activity: Gram-positive pathogens including MRSA, vancomycin-resistant
enterococci, vancomycin-resistant staphylococci, drug-resistant S. pneumoniae, and
linezolid-resistant gram-positive pathogens
(c) PK and dosing
(1) Bioavailability 91% – Can be administered as a parenteral solution or oral tablets
(2) Half-life: 12 hours
(3) Dosing: 200 mg once daily
(d) Studies: Tedizolid once daily for 6 days was compared with linezolid twice daily for 10
days for the treatment of acute bacterial skin and skin structure infection and was found
to be noninferior.
(e) Application: Place in therapy among critically ill patients is limited. Studies are under way
for the use of tedizolid in the treatment of hospital-acquired pneumonia.
iii. Ceftaroline
(a) Antimicrobial class: Fifth-generation cephalosporin
(b) Spectrum of activity: Enterobacteriaceae (similar to third-generation cephalosporins) and
gram-positive pathogens, including MRSA, drug-resistant S. pneumoniae, and vancomycin-
intermediate and vancomycin-resistant staphylococci
(c) PK and dosing
(1) Activity against MRSA mediated through enhanced affinity to penicillin-binding-
protein 2a
(2) Half-life: 2.7 hours
(3) Excretion: 88% urine
(4) Dosing:
(A) 600 mg intravenously every 12 hours is the FDA label-approved dosing. Reports
of using 600 mg intravenously every 8 hours for severe infections
(B) Adjustments necessary for patients with renal impairment
(d) Studies:
(1) Evaluated in a noninferiority trial compared with ceftriaxone, both in conjunction with
clarithromycin, for the treatment of community-acquired bacterial pneumonia. Results
indicated noninferiority, with numerically higher cure rates in those randomized to
ceftaroline. Clinical response by day 4 of therapy was also higher in the ceftaroline
group.
(2) Evaluated in a noninferiority trial compared with vancomycin plus aztreonam for the
treatment of skin and skin structure infection. Ceftaroline cure rates were within the a
priori–determined margin, thus satisfying the criteria for noninferiority.
(e) Application:
(1) FDA approved for acute bacterial skin and skin structure infections and community-
acquired bacterial pneumonia
(2) Despite its FDA approvals, the main role of ceftaroline is the availability of an
additional agent with activity against MRSA. May be an option when vancomycin
therapy is suboptimal and other treatment options may lead to unwanted adverse
effects. May also be a reasonable option for the treatment of community-acquired
pneumonia in institutions where community-acquired MRSA is common.
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Patient Case
6. A 72-year-old woman with a history of end-stage renal disease is admitted to the medical ICU with signs and
symptoms of sepsis. Blood cultures are obtained in which two of two bottles grow gram-positive cocci. The
patient is initiated on vancomycin, and her tunneled dialysis catheter is removed. On day 4 of therapy, the
blood cultures are finalized to be MRSA with the following antibiotic susceptibility results: oxacillin greater
than 4 mcg/mL – R; vancomycin 2 mcg/mL – S; daptomycin 0.5 mcg/mL – S; and linezolid 1 mcg/mL – S.
A transthoracic echocardiogram is obtained, which reveals echodensities on the mitral valve. The patient
will be treated medically with antibiotics for 4–6 weeks. The patient’s repeat blood cultures are currently
no-growth. Her vital signs and laboratory values are as follows: blood pressure 150/90 mm Hg, heart rate
88 beats/minute, temperature 100.2°F, WBC 11 x 103 cells/mm3, and lactate 1.1 mmol/L. Which is the most
appropriate treatment regimen?
A. Change vancomycin to linezolid 600 mg every 12 hours.
B. Add gentamicin and rifampin to vancomycin.
C. Change vancomycin to daptomycin 6 mg/kg every 48 hours.
D. Continue vancomycin and target a trough level of 15–20 mcg/mL.
VII. IMMUNOCOMPROMISED PATIENTS
A. Febrile Neutropenia
1. Definition
a. Fever: A single temperature of 100.9°F (38.3°C) or greater orally or a temperature of 100.4°F
(38.0°C) or greater orally for more than 1 hour
b. Neutropenia: Less than 500 neutrophils/mm3 or less than 500 neutrophils/mm3 during the next 48
hours
2. Patients with neutropenic fever admitted to an ICU should be considered high risk.
3. Initial therapy should include monotherapy with an intravenous antipseudomonal β-lactam (i.e., cefepime,
piperacillin/tazobactam, meropenem, imipenem).
a. Most patients with an allergy to β-lactams tolerate cephalosporins and carbapenems.
b. Patients with type 1 hypersensitivity should be treated with either ciprofloxacin or aztreonam plus
vancomycin.
4. Consider dual gram-negative therapy (fluoroquinolone or aminoglycosides) in patients with shock or if
antimicrobial resistance is suspected.
5. Consider adding vancomycin to gram-negative therapy in patients with shock, suspected catheter-related
infection, skin and soft tissue infection, and/or pneumonia. Gram-positive therapy can be discontinued
in 48–72 hours if no evidence of gram-positive infections is discovered.
6. Modifications to initial antibiotic choices should be considered for patients with worsening clinical status
or if patients’ microbiological data warrant change.
7. Unexplained persistent fever in an otherwise clinically stable patient rarely warrants an escalation in
therapy. Persistent fevers for 4–7 days after initiation of antibacterial agents should warrant consideration
for empiric antifungal coverage in those who have persistent neutropenia.
8. Initial antimicrobials should be de-escalated or escalated in documented infections depending on in
vitro susceptibility. Documented infections and unexplained fevers should be treated for a minimum of
14 days and until the absolute neutrophil count is greater than 500 cells/mm3.
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9. Patients with hemodynamic instability should have their initial antibiotic regimen escalated to include
coverage for resistant bacteria and fungi.
10. Hematopoietic growth factors should not be used for the treatment of febrile neutropenia. Prophylactic
use of hematopoietic growth factors should be considered for patients with a high anticipated risk of
febrile neutropenia (20% or greater).
B. Solid Organ Transplantation

1. Epidemiology
a. Hospital-acquired bacterial infections are the most common types of infections in SOT recipients.
b. 50%–75% of SOT recipients will experience an infection within the first year after transplantation.
c. Posttransplant infections may contribute to graft dysfunction and reduce long-term survival, and
they have been associated with prolonged LOS and cost of care.
d. An analysis of 60,000 renal transplant recipients found that infections were the second leading
cause of death.
2. General risk factors for infections
a. Excessive use of antibiotics before transplantation: With the use of prophylactic antimicrobials in
the pretransplant period, many transplant recipients are experiencing resistant pathogens in the
posttransplant period.
b. Infections are most common in the first 6 months after transplantation, with different pathogens
presenting after various durations of immunosuppression. See Figure 4. OIs are rare in the first
month after transplantation because the full effects of immunosuppression are not yet present.
Fungal and viral infections experienced during the first month after transplantation are usually
donor derived.
c. Duration of hospitalization after transplantation
d. Renal dysfunction
e. Several acute rejection episodes
3. General clinical approach for infectious diseases issues in critically ill SOT recipients
a. Be cognizant of the patient’s transplant timeline, particularly with respect to possible OIs,
pretransplant risk factors, immune status, intensity of immunosuppressive therapy, prophylactic
regimens, and recent treatments of rejection.
b. Have a high clinical suspicion for OIs.
c. Severe infections sometimes warrant a reduction in maintenance immunosuppression. Consult with
the transplant team regarding plans for maintenance immunosuppression.
d. Be aware of the many drug interactions between immunosuppressants and antimicrobials.
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Conventional
Community-acquired
nosocomial Unconventional or opportunistic infections
persistent infections
infections
Viral
HSV
Onset of CMV CMV retinitis or colitis
EBV, VZV, influenza, RSV, adenovirus
Papillomavirus, PTLD
Onset of hepatitis B or hepatitis C
Bacterial
Wound infections, catheter-related infections, pneumonia
Nocardia
Listeria, tuberculosis
Fungal
Pneumocystis
Aspergillus Cryptococcus
Candida Endemic fungi
Parasitic
Strongyloides
Toxoplasma
Leishmania
Trypanosoma cruzi
0 1 2 3 4 5 6
Months After Transplant
Figure 4. Usual sequence of infections after organ transplantation.a

a
Zero indicates the time of transplantation. Solid lines indicate the most common period for the onset of infection; dotted lines indicate periods of continued
risk at a reduced level.
CMV = cytomegalovirus; EBV = Epstein-Barr virus; HSV = herpes simplex virus; PTLD = posttransplant lymphoproliferative disease; RSV = respiratory
syncytial virus; VZV = varicella-zoster virus.
Reproduced with permission from: Baillie GM. Infectious disease concerns in solid organ transplantation. In: Schumock GT, Brundage DM, Dunsworth TS,
et al., eds. Pharmacotherapy Self-Assessment Program, 5th ed. Book 2. Transplantation. Lenexa, KS: American College of Clinical Pharmacy, 2004:165-86.
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VIII. HUMAN IMMUNODEFICIENCY VIRUS/ACQUIRED IMMUNE DEFICIENCY SYNDROME IN

CRITICALLY ILL PATIENTS
A. Diagnosis
1. Isolated CD4+ lymphopenia has occurred in critically ill patients without HIV disease.
a. Differential diagnosis of CD4+ lymphopenia
i. Idiopathic
ii. Common variable immunodeficiency
iii. Corticosteroid administration
iv. Circadian rhythm
v. Hematologic malignancies
vi. Critical illness
2. Patients with traditional HIV risk factors, isolated CD4+ lymphopenia, or AIDS-defining OIs who
have not been given a diagnosis should receive HIV serologic testing. See Table 10 for AIDS-defining
conditions.
B. Presentation for HIV-Associated Acute Illness

1. Changing prescribing patterns in highly active antiretroviral therapy (HAART) and improvements in
care have changed the landscape of ICU admissions associated with HIV. Although the utility of ICU
over time among HIV-positive patients has not decreased, the rationale for ICU admission has shifted
from respiratory distress associated with pneumocystic pneumonia to other sepsis etiologies, neurologic
disorders, and other end-organ dysfunctions.
2. See Table 11 for the management and prophylaxis of commonly occurring OIs in critically ill patients.
C. Management of HAART Therapy

1. Treatment-naive patient
a. Initiation of HAART in an ICU may be deterred by factors such as lack of oral access, inability
to assess the patient’s willingness to commit to therapy, and high probability of interruptions in
therapy because of surgical interventions.
b. Immune reconstitution inflammatory syndrome
i. Unexpected worsening of existing OI or unmasking of previously unrecognized illness
associated with recent HAART initiation
ii. Recovery of immune response leading to a proinflammatory cytokine storm
iii. Risk factors
(a) Presence of disseminated disease or high antigen load
(b) High baseline HIV viral load
(c) Rapid response to antiretroviral therapy
iv. Evidence does not suggest that early administration of HAART (at the onset of an AIDS-
defining OI) is associated with a higher incidence of immune reconstitution inflammatory
syndrome.
2. Patient receiving HAART regimen
a. Considerations: Availability of drug formulations conducive to ICU administration; food
requirements; dose adjustments associated with renal or hepatic impairment; new drug interactions;
possible interruptions in therapy
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b. In general, if one of the antiretroviral therapies needs to be discontinued, all of the therapies should
be discontinued to decrease the promotion of resistance caused by the suboptimal suppression of
viral replication. Exceptions: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have long
half-lives (as long as 3 weeks); therefore, if NNRTIs are discontinued at the same time as other
antiretrovirals with shorter half-lives, there will be a period of functional NNRTI monotherapy. May
consider continuing antiretrovirals with shorter half-lives, if possible, for 1–2 weeks to minimize
selection of NNRTI resistance.
c. Possible ICU drug interactions – See Table 12.
3. HAART-associated adverse drug reactions
a. Newer generations of HAART regimens are generally well tolerated; however, many patients still
receive older HAART therapy.
b. Many of the HAART-associated adverse effects have no specific treatment; therefore, early
recognition and prompt discontinuation of the offending agent is crucial.
c. Lactic acidosis
i. Two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remain the backbone of
many HAART regimens.
ii. NRTIs are associated with a variety of mitochondrial toxicities.
iii. Older NRTIs such as zidovudine, stavudine, and didanosine have been associated with lactic
acidosis.
iv. Symptoms: Fatigue, malaise, nausea, vomiting, abdominal pain, hepatomegaly
v. Management: Supportive therapy and discontinuing the potential offending agent
d. Abacavir hypersensitivity
i. Symptoms: Fever, rash, gastrointestinal (GI) symptoms
ii. Reaction associated with the presence of the HLA-B*5701 allele, which has an 8% prevalence
among whites in North America. Genetic screening for allele is recommended.
iii. Management: Supportive care and discontinuing agent, with re-challenge contraindicated
because of the possibility of life-threatening hemodynamic compromise
e. Other HAART-associated significant adverse effects:
i. Nevirapine hypersensitivity: Rash (may progress to Stevens-Johnson syndrome), fever,
hepatotoxicity
ii. Raltegravir-associated rhabdomyolysis
iii. Tipranavir-associated hepatotoxicity and intracranial hemorrhage
iv. Protease inhibitor–associated pancreatitis
D. Management and Prophylaxis of HIV-Associated Infections: See Table 10.
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Patient Case
7. A 46-year-old man is admitted to the medical ICU for diabetic ketoacidosis. The patient has a history of
insulin-dependent diabetes, is HIV positive, and has cryptococcal meningitis. His current HAART regimen
consists of atazanavir, ritonavir, tenofovir, and emtricitabine, which is continued on admission to the ICU.
The patient’s CD4+ count is 85/mm3. The patient’s diabetic ketoacidosis is well controlled, and he is ready to
be discharged from the ICU. Before discharge, the patient is noted not to be on any prophylaxis against OIs.
Which prophylactic regimen would be most appropriate for the patient?
A. Azithromycin 1200 mg once weekly and trimethoprim/sulfamethoxazole 1 double-strength (DS) tablet
thrice weekly.
B. Fluconazole 200 mg daily and trimethoprim/sulfamethoxazole 1 DS tablet daily.
C. Azithromycin 1200 mg once weekly and fluconazole 200 mg daily.
D. Fluconazole 200 mg daily and trimethoprim/sulfamethoxazole 1 DS tablet thrice weekly.
Table 10. AIDS-Defining Conditions
Bacterial infections, multiple/recurrent (< 13 yr) Lymphoid interstitial pneumonia or pulmonary

Candidiasis: Bronchi, trachea, or lungs lymphoid hyperplasia complex (< 13 yr)
Candidiasis: Esophageal Lymphoma: Burkitt (or equivalent term)
Cervical cancer: Invasive Lymphoma: Immunoblastic (or equivalent term)
Coccidioidomycosis: Disseminated or Lymphoma: Primary or brain
extrapulmonary Mycobacterium avium complex or M. kansasii:
Cryptococcosis: Extrapulmonary Disseminated or extrapulmonary
Cryptosporidiosis: Chronic intestinal (for > 1 mo) M. tuberculosis: Any site (pulmonary or
Cytomegalovirus disease extrapulmonary)
(other than the liver, spleen, or nodes) Mycobacterium: Other species or unidentified
Cytomegalovirus retinitis (with loss of vision) species; disseminated or extrapulmonary
Encephalopathy: HIV related Pneumocystis jiroveci pneumonia
Herpes simplex: Chronic ulcer(s) Pneumonia: Recurrent
(for > 1 mo); bronchitis, pneumonitis, Progressive multifocal leukoencephalopathy
or esophagitis Salmonella septicemia (recurrent)
Histoplasmosis: Disseminated or extrapulmonary Toxoplasmosis of brain
Isosporiasis: Chronic intestinal Wasting syndrome caused by HIV
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Table 11. AIDS-Associated OIs and Their Respective Prophylactic and Treatment Options
OI/CD4+ Threshold
for Prophylaxis Prophylaxis Option Treatment Option
Preferred:
Preferred:
TMP/SMXb 15–20 mg/kg PO/IV divided q6–8hr x 21
TMP/SMXb 1 DS PO daily
days
or
plus
TMP/SMXb 1 SS PO daily
prednisone 40 mg PO q12hr x 5 days; 40 mg/day x 5 days;
Alternatives 20 mg/day x 11 days
Pneumocystis jiroveci: 1. Dapsone PO 100 mg/ (if Pao2< 70 mm Hg or alveolar-arterial O2 gradient > 35)
a
< 200 cells/mm3 day (IV methylprednisolone could be administered at 75% of

2. Pentamidine 300 mg dose)
inhalation once monthly
Alternatives:
3. TMP/SMX 1 DS PO
1. Pentamidineb IV 4 mg/kg/day
TIW
2. Clindamycin 600–900 mg PO/IV q6–8hr +
4. Atovaquone PO 1500
primaquinea PO 30 mg/day (base)
mg/day
3. Atovaquone 750 mg PO q12hr
Preferred:
Preferred: Pyrimethamineb 200 mg PO x 1; then 50–75 mg/day +
TMP/SMX 1 DS PO daily sulfadiazineb 1000–1500 mg PO q6hr + leucovorin PO
Toxoplasmosis: 10–20 mg/day x 6 wk
Alternatives:
< 100 cells/mm3 1. Dapsonea PO 50 mg/day Alternatives:
and Toxoplasma IgG + (pyrimethamine 50 mg 1. Pyrimethamineb 200 mg PO x 1; then 50–75 mg/day
positive PO + leucovorin 25 mg + clindamycin 600–900 mg PO/IV q8hr + leucovorin
PO) once weekly PO 10–20 mg/day
2. TMP/SMX 1 DS PO 2. Pyrimethamineb 200 mg PO x 1; then 50–75 mg/day +
TIW atovaquone 1500 mg PO BID + leucovorin PO 10–20
mg/day
Preferred:
Azithromycin 1200 mg Preferred:
once weekly At least two drugs: Clarithromycin 500 mg PO BID or
or azithromycin 600 mg/day
plus ethambutolb PO 15–25 mg/kg/day
Mycobacterium avium Clarithromycin 500 mg
q12hr Additional agents (consider depending on susceptibility
complex:
or testing, severe disease, or low CD4+ count)
< 50 cells/mm3
Azithromycin 600 mg Rifabutinc PO 300 mg/day
twice weekly Amikacinb IV 10–15 mg/kg/day
fluoroquinolones (moxifloxacin PO/IV 400 mg/day or
Alternatives: levofloxacinb PO/IV 500 mg/day)
Rifabutinc 300 mg/day
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Table 11. AIDS-Associated OIs and Their Respective Prophylactic and Treatment Options (continued)
OI/CD4+ Threshold
for Prophylaxis Prophylaxis Option Treatment Option
Latent infection treatment
Preferred:
Isoniazid (INH) PO 300 Active infection treatment
Mycobacterium
mg/day + pyridoxine PO Preferred:
tuberculosis: Primary
50 mg/day Rifampinc PO/IV 600 mg/day + INH PO 300 mg/day +
prophylaxis not
indicated Alternatives: pyrazinamideb PO 20–25 mg/kg/day + ethambutolb PO
INH 900 mg PO twice 15–25 mg/kg/day
weekly + pyridoxine
100 mg PO twice weekly
Preferred:
Induction therapy x 2 wk:
Liposomal amphotericin IV 3-4 mg/kg/day + flucytosineb
PO 25 mg/kg q6hr
Cryptococcosis: Alternatives:
Primary prophylaxis Induction x 2 wk:
not indicated Secondary prophylaxis: 1. Amphotericin B IV 0.7–1 mg/kg/day + flucytosineb
Fluconazole 200–400 mg/ PO 25 mg/kg q6hr
Secondary day 2. Amphotericin B lipid complex 3-4 mg/kg/day +
prophylaxis may be flucytosineb PO 25 mg/kg q6hr
considered 3. Liposomal amphotericin IV 3–4 mg/kg/day +
fluconazoleb 800 mg PO/IV daily
Preferred:
Consolidation therapy x 8 wk
Fluconazole PO/IV 400 mg/day
Preferred:
Cytomegalovirus: Induction:
Primary prophylaxis Valganciclovirb PO 900 mg BID for 14–21 days
Secondary prophylaxis: or
not indicated
Valganciclovirb PO 900 mg/ Ganciclovirb 5 mg/kg q12hr for 14–21 days
Secondary
day
prophylaxis may be Alternatives:
considered 1. Foscarnetb IV 90 mg/kg q12hr or 60 mg/kg q8hr
2. Cidofovir IV 5 mg/kg/wk
a
Should not be used in patients with a glucose-6-phosphate dehydrogenase deficiency.
b
Renal adjustments may be necessary.
c
Monitor for interactions with HAART.
BID = twice daily; DS = double strength; h = hour(s); INH = isoniazid; OI = opportunistic infection; PO = orally; SS = single strength; TIW = thrice weekly;
TMP/SMX = trimethoprim/sulfamethoxazole.
Reproduced with permission from: Smith CL. HIV/infectious disease. In: ACCP Updates in Therapeutics® 2014: Pharmacotherapy Preparatory Review and
Recertification Course. Lenexa, KS: American College of Clinical Pharmacy, 2014:580-621.
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Table 12. Common Interactions Between Antiretrovirals and Commonly Used Medications in Critically Ill Patients
Agent Antiretroviral Interactions
Rilpivirine: Contraindicated with proton
pump inhibitors
Stress ulcer prophylaxis
(proton pump inhibitors, Atazanavir: Relatively contraindicated
with proton pump inhibitors (administer Decrease in antiretroviral concentrations
histamine-2 receptor
antagonists) no more than the equivalent of
omeprazole 20 mg daily, and separate
administration by at least 12 hr)
Triazole antifungals:
Protease inhibitors:
Voriconazole, Increase in antiretroviral concentration
Nonnucleoside reverse transcriptase
posaconazole, Decrease in antifungal concentrations
inhibitors
itraconazole
Antibacterials:
Rifampin Protease inhibitors: Decrease in antiretroviral concentration
inhibitors
Clarithromycin Protease inhibitors Increase in clarithromycin concentration
inhibitors
Metronidazole Fosamprenavir, lopinavir, ritonavir Disulfiram reaction
Antiarrhythmics:
Amiodarone Indinavir, ritonavir, tipranavir
Flecainide, Lopinavir, ritonavir, tipranavir Increased antiarrhythmic concentrations
propafenone, quinidine
Diltiazem Atazanavir, fosamprenavir
Increase concentrations of statins –
Protease inhibitors
in decreasing order of interaction
Statins Nonnucleoside reverse transcriptase
potential (lovastatin, simvastatin,
inhibitors
rosuvastatin, atorvastatin, pravastatin)
Anticonvulsants: Protease inhibitors Increase in antiretroviral concentrations
Carbamazepine, Nonnucleoside reverse transcriptase Decrease in anticonvulsant
phenobarbital, phenytoin inhibitors concentrations
Protease inhibitors
Midazolam Increase in midazolam concentration
inhibitors
Cobicistat/elvitegravir
inhibitors; fosamprenavir, ritonavir,
Methadone Opioid withdrawal
lopinavir, nelfinavir, didanosine,
saquinavir
Sildenafil Protease inhibitors; delavirdine Increase in sildenafil concentration
Warfarin Delavirdine, efavirenz Increase in warfarin concentration
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IX. ANTIFUNGAL THERAPY
A. Amphotericin B
1. Mechanism of action: Binds to ergosterol in the fungal cell membrane, which alters the membrane
permeability, leading to ion leakage and fungal cell death
2. Spectrum of activity
a. Candida spp. (except for C. lusitaniae), blastomycetes, coccidioidomycosis, Cryptococcus,
Paracoccidioides, histoplasmosis, aspergillosis, mucormycosis
b. Wide spectrum of activity allows its clinical use in many different systemic fungal infections.
3. Dose
a. Conventional amphotericin: 0.5–1.0 mg/kg/day
b. Lipid amphotericin: 3–5 mg/kg/day (higher doses have not been associated with improved outcomes)
4. Adverse effects
a. Renal toxicity
i. Decrease in glomerular filtration rate, which is associated with cumulative doses greater than
4–5 g
ii. Clinical manifestation
(a) Renal tubular acidosis
(b) Oliguria
(c) Azotemia
(d) Potassium, magnesium, phosphate wasting
iii. Prevention
(a) Avoid concomitant nephrotoxins.
(b) Avoid dehydration.
(c) Salt loading: 500 mL of normal saline before and after infusion of amphotericin
b. Infusion-related reactions
i. Mediated by cytokine release and prostaglandin synthesis
ii. Presentation: Fever, chills, nausea, vomiting, flushing, rigors
iii. Prevention
(a) Premedications – Administered 30–60 minutes before infusion
(1) Hydrocortisone 25–50 mg
(2) Ibuprofen 600 mg
(3) Acetaminophen 650 mg with diphenhydramine 50 mg
(4) Meperidine 50 mg if patient previously experienced rigors
(b) Use lower infusion rate on dose initiation.
c. Lipid amphotericin (liposomal amphotericin and amphotericin B lipid complex)
i. Amphotericin dissociates from lipid over time, which may limit its renal toxicity and infusion-
related reactions.
ii. Premedication may still be necessary for amphotericin B lipid complex.
B. Triazole Antifungals
1. Mechanism of action: Inhibits the synthesis of ergosterol through blocking the CYP enzyme 14-α-sterol-
demethylase. Inhibition of this enzyme leads to the accumulation of 14-α-methyl sterols on the fungal
surface, which in turn leads to fungal cell death.
2. Fluconazole
a. Spectrum of activity:
i. Candida spp.
(a) C. krusei is intrinsically resistant.
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(b) Variable sensitivity with C. glabrata. Should not be used for C. glabrata unless antifungal
susceptibilities are available. If C. glabrata is sensitive dose-dependent, higher doses may
be necessary (12 mg/kg/day).
(c) Good activity against all other pathogenic Candida spp.
ii. Cryptococcus
b. Dose
i. 6–12 mg/kg/day (400–800 mg/day)
ii. Available in intravenous and oral formulations
iii. Well absorbed orally with high bioavailability
iv. Primarily excreted by the kidneys – Renal dose adjustments are necessary.
c. Adverse effects: Minimal adverse effects and lowest propensity for drug interactions among triazoles
3. Itraconazole
a. Spectrum of activity
i. Candida spp. – Has coverage similar to fluconazole with the exception of activity against C. krusei
ii. Aspergillus, Blastomyces, Histoplasma
b. Dose
i. 200–400 mg once daily
ii. Intravenous formulation no longer available
iii. Poor and erratic oral absorption. Improved with oral liquid formulation, maintaining high
stomach acidity, avoidance of acid-suppressive therapy, and coadministration with acidic
beverage
iv. Therapeutic drug monitoring may be necessary. Target: Itraconazole plus hydroxy-itraconazole
concentration greater than 1 mcg/mL
v. Primarily used for fungal prophylaxis in immunocompromised patients and treatment of
endemic fungi (histoplasmosis)
c. Adverse effects
i. GI upset, increase in liver function tests
ii. Drug interactions: CYP 3A4 and 2C9 inhibitor
4. Voriconazole
a. Spectrum of activity
i. Candida spp. – Has coverage similar to fluconazole with the exception of activity against C. krusei
ii. Aspergillus, Fusarium, Scedosporium: Resistance against voriconazole has occurred with these
pathogens.
b. Dose
i. Drug of choice for invasive aspergillosis
ii. 6 mg/kg every 12 hours x 2 doses as the loading dose, followed by 4 mg/kg every 12 hours
iii. Intravenous and oral formulations are available.
iv. Intravenously formulated in sulfobutyl-ether-β-cyclodextrin, which accumulates in renal
dysfunction, although the clinical significance of this is unknown
v. Extensively metabolized by the liver, with 50% dose reductions recommended for patients with
moderate to severe cirrhosis
vi. Genetic variations in CYP metabolism and high propensity for drug interactions lead to wide
interpatient variability in concentrations.
vii. Therapeutic drug monitoring may be necessary. Target concentration: 1–5.5 mcg/mL
c. Adverse reactions
i. Increase in liver function tests
ii. Visual hallucinations
iii. Rash
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iv. Nausea
v. CYP 3A4 and 2C9 inhibitor:
(a) Contraindicated with the use of rifampin, rifabutin, sirolimus, barbiturates, carbamazepine,
and quinidine
(b) Significant dose reductions for cyclosporine and tacrolimus when coadministered with
voriconazole
5. Posaconazole
a. Spectrum of activity: Wide spectrum of activity, which includes Candida (similar to voriconazole),
Aspergillus, Zygomycetes, and Fusarium
b. Dose
i. Oral suspension (immediate release): 200 mg every 6 hours. Oral suspension has extremely
erratic absorption that is enhanced by coadministration with a high-fat meal and acidic food.
In critically ill patients in whom coadministration with fatty meals and avoidance of acid-
suppressive stress ulcer prophylaxis cannot be avoided, would recommend considering an
alternative therapy or administration method (e.g., oral tablets or intravenous)
ii. Oral tablets (delayed release): 300 mg every 12 hours x 2 doses, followed by 300 mg once
daily. Oral tablet is in an extended-release formulation, which cannot be crushed. Oral tablet
absorption not as dependent on gastric pH and meal lipid content
iii. Intravenous: 300 mg every 12 hours x 2 doses, followed by 300 mg once daily (intravenously
formulated in sulfobutyl-ether-β-cyclodextrin, which accumulates in renal dysfunction,
although the clinical significance of this is unknown)
iv. Therapeutic drug monitoring may be prudent, particularly when oral suspension is used. Target
concentrations: Greater than 1.25 mcg/mL for treatment of invasive fungal infection
v. Mainly used for fungal prophylaxis in immunocompromised patients and treatment when
patient is not responding to other therapies
c. Adverse reactions
i. Increase in liver function tests
ii. Nausea/vomiting
iii. Drug interaction: CYP3A4 inhibitor
6. Isavuconazole
a. Spectrum of activity: Wide spectrum of activity, including Candida (similar to voriconazole),
Aspergillus (may retain activity for some species that are resistant to other azoles), Zygomycetes,
and dimorphic fungi. Limited activity against Fusarium
b. Dose
i. Intravenous or oral: 372 mg of isavuconazonium sulfate (equivalent to 200 mg of isavuconazole)
every 8 hours, after a 1116-mg (600 mg of isavuconazole) loading dose
ii. Isavuconazonium sulfate solution is readily water soluble, unlike posaconazole and voriconazole,
and does not require stabilization with cyclodextrin.
c. Mainly PK advantages and safety benefits over voriconazole and posaconazole
i. Linear kinetics
ii. Oral bioavailability: 98%, not affected by food or acidity
iii. Fewer drug-drug interactions
iv. No QTc prolongation; in fact, associated with dose-dependent QTc shortening
C. Echinocandins (caspofungin, micafungin, and anidulafungin)

1. Mechanism of action: Inhibition of glucan synthase, which is an enzyme responsible for the formation of
1,3-β-d-glucan. Inhibition of this enzyme leads to cessation of fungal cell wall formation.
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2. Spectrum of activity: All Candida spp. and Aspergillus

a. In vitro, C. parapsilosis has a much higher MIC than other Candida spp. The clinical significance
of this is unknown. Cases of breakthrough infections with C. parapsilosis during treatment with
echinocandins have been reported. Several retrospective studies did not find worsened outcomes
associated with echinocandin treatment of C. parapsilosis. The current IDSA guidelines on invasive
candidiasis recommend using fluconazole for the treatment of C. parapsilosis.
b. Primarily used for invasive candidiasis, neutropenic fever, and invasive Aspergillus if patient cannot
tolerate other therapies
3. Dose (available only as an intravenous formulation)
a. Caspofungin: 70 mg once, followed by 50 mg once daily
b. Micafungin: 100 mg once daily
c. Anidulafungin: 200 mg once, followed by 100 mg once daily
4. Adverse reactions
a. Well tolerated with minimal GI adverse effects
b. Minimal drug interactions
i. Avoid caspofungin coadministration with cyclosporine and tacrolimus.
ii. Avoid micafungin coadministration with nifedipine and sirolimus.
iii. Avoid administering anidulafungin with metronidazole (disulfiram reaction).
D. Flucytosine
1. Mechanism of action: Converted by fungal enzymes to fluorouracil, which disrupts fungal RNA and
DNA synthesis
2. Spectrum of activity
a. Candida spp.
b. Cryptococcus: Treatment of choice (in conjunction with amphotericin) for Cryptococcus
3. Dose
a. 37.5 mg/kg every 6 hours
b. Renal adjustments necessary
c. Well absorbed: Bioavailability 80%–90%
d. Available only as an oral formulation in the United States
e. Therapeutic concentrations: 25–100 mcg/mL
4. Adverse reactions: Bone marrow suppression, particularly with supratherapeutic concentrations
Patient Case
8. A 66-year-old woman (height 66 inches, weight 75 kg) is admitted to the medical ICU for dehydration and acute
kidney injury. The patient recently received an allogeneic bone marrow transplant and has not yet engrafted.
She has been pancytopenic for 12 days. On day 5 of the medical ICU stay, the patient develops acute respiratory
distress requiring intubation. Bronchoalveolar lavage is done, which eventually grows A. fumigatus, and the
patient is given a diagnosis of invasive pulmonary aspergillosis. The patient’s current medications include
tacrolimus, corticosteroids, and fluconazole fungal prophylaxis. Her current relevant laboratory values are as
follows: WBC 0.2 x 103 cells/mm3, lactate 1.5 mmol/L, and SCr 3.4 mg/dL. Which antifungal therapy is most
appropriate?
A. Amphotericin 50 mg intravenously once daily.
B. Isavuconazole load follow by 200 mg intravenously every 8 hours.
C. Caspofungin load, followed by 50 mg intravenously daily.
D. Voriconazole load followed by 300 mg intravenously every 12 hours.
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ANSWERS AND EXPLANATIONS TO PATIENT CASES
1. Answer: D case, and antibiotics should be continued to cover the

The CDC definitions for CAUTIs, which are used by the most likely pathogens (Answer B is incorrect). Because
CMS reporting system, were recently updated. Because the patient is admitted with presumed community-
this patient had his urinary catheter removed for more acquired pneumonia, the combination of ceftriaxone
than 24 hours before developing UTI symptoms, this and azithromycin is appropriate right now (Answer A is
case does not satisfy the definition of CAUTI (Answer D correct, and Answer C and D are incorrect).
is correct; Answers A and C are incorrect). The current
CDC CAUTI definitions do not consider the results of a 5. Answer: B
urinalysis (Answer B is incorrect). This patient is being treated for an ESBL E. coli UTI,
in which the source of the infection (urinary catheter)
2. Answer: A is removed. The patient also has signs of response to
This patient presents with community-acquired piperacillin/tazobactam with resolution of leucocytosis
meningitis. The high opening pressure is suggestive of a and fever. In this case, given the low inoculum of the
bacterial etiology, of which the most prevalent pathogen infection, initial response, removal of source, and low
for this patient’s risk factors and age is S. pneumoniae. MIC, continuing piperacillin/tazobactam is the best choice
Administering dexamethasone before initiating (Answer B is correct). Traditionally, it was widely believed
antibiotic therapy decreases mortality in patients with S. that ESBL infections had to be treated with carbapenems.
pneumoniae meningitis. (Answer A is correct) Awaiting However, recent evidence suggests that β-lactam/β-
laboratory and microbiologic test results analysis lactamase inhibitor combinations are a suitable option.
may cause inappropriate delays in therapy (Answer In the era of antimicrobial stewardship, the preservation
B is incorrect). In addition, although administering of carbapenem therapy should be regarded with high
antimicrobials is a good idea, the beneficial effects importance (Answer A is incorrect). This current culture
associated with dexamethasone are diminished if has an MIC of 4 mcg/mL to cefepime, which, according
administered after antimicrobials have been initiated. to the updated CLSI guidelines, would be considered
At the very least, corticosteroids should be administered resistant (Answer C is incorrect). Because the patient is
concomitantly with antimicrobials (Answer C and D are responding to the current therapy, combination therapy is
incorrect). unnecessary (Answer D is incorrect).
3. Answer: D 6. Answer: D
The PNA FISH technology is designed to identify This patient is being treated for MRSA right-sided
pathogens earlier. It performs well, with good sensitivity endocarditis, with the presumed source from her tunneled
and specificity; hence, identification of C. parapsilosis dialysis catheter. According to the IDSA guidelines for
should not require verification from culture. The drug of the treatment of MRSA, treatment with vancomycin
choice for the treatment of C. parapsilosis is fluconazole of an isolate with an MIC of 2 mcg/mL or less should
(Answer D is correct). Although echinocandin, be determined by the patient’s response to therapy,
voriconazole, and amphotericin would all cover C. regardless of the actual MIC. This patient has responded
parapsilosis, they all have a broader spectrum than is to therapy with the presumed clearance of blood cultures
necessary, making them not the ideal choice (Answers and resolution of signs and symptoms of infection.
A–C are incorrect). Hence, continuing vancomycin and targeting a trough of
15–20 mcg/mL is the most appropriate choice (Answer D
4. Answer: A is correct). Linezolid is not indicated for the treatment of
Although PCT is a promising biomarker for the detection endocarditis (Answer A is incorrect). Adding gentamicin
of bacterial infections, it must be interpreted within the and rifampin is considered in the medical treatment of
context of the patient’s clinical course. In this case, prosthetic valve endocarditis (Answer B is incorrect).
the patient has clear signs and symptoms of infection, Because the patient is responding to current vancomycin
together with signs of hypoperfusion. A low PCT should therapy, an escalation to daptomycin is inappropriate
not be used to guide therapy discontinuation in this right now (Answer C is incorrect).
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7. Answer: B
This patient is admitted to the ICU for an indication
that is unrelated to the patient’s underlying HIV. The
assessment of which prophylactics are necessary against
OIs depends on the patient’s underlying disease, history,
and CD4+ count. In this case, the patient has a CD4+
count less than 100/mm3 and a history of cryptococcal
meningitis. Hence, prophylaxis should be administered
for toxoplasmosis, P. jiroveci, and Cryptococcus. The
best regimen for this patient is fluconazole 200 mg
daily and trimethoprim/sulfamethoxazole 1 DS tablet
once daily (Answer B is correct). The prophylaxis for
Mycobacterium avium complex is indicated for patients
with a CD4+ count of less than 50 cells/mm3, which
is unnecessary at this point (Answers A and C are
incorrect). Although trimethoprim/sulfamethoxazole 1
DS tablet thrice weekly is an option for prophylaxis, it
is not the best choice against toxoplasmosis (Answer D
is incorrect).
8. Answer B
This patient has invasive pulmonary aspergillosis.
Usually, the treatment of choice is voriconazole.
However, in this case, the patient has acute kidney
injury with a CrCl less than 50 mL/minute/1.73 m2.
According to the package insert, voriconazole is
contraindicated in this case because of the possibility
of accumulation of cyclodextrin, the intravenous drug
carrier for voriconazole. Although the clinical relevance
of this accumulation is controversial, continued use
of a contraindicated therapy is inappropriate when
alternatives may be available (Answer C is incorrect).
Isavuconazole is a new triazole that was found to
be noninferior to voriconazole for the treatment of
aspergillosis and has improved water solubility, which
does not require it to be formulated with cyclodextrin
(Answer B is correct). Conventional amphotericin may
be a reasonable choice, but it will likely worsen the
patient’s acute kidney injury (Answer A is incorrect).
Echinocandins are not the ideal therapies for invasive
aspergillosis and should only be considered if there are
no other treatment options (Answer D is incorrect).
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ANSWERS AND EXPLANATIONS TO SELF-ASSESSMENT QUESTIONS
1. Answer: C pathogens include MRSA and multidrug-resistant

The prophylactic regimen for a patient without a β-lactam gram-negative organisms. In addition to neurosurgical
allergy who is undergoing cardiac surgery should management of the device (e.g., removal or revision),
be cephalosporin administered within 60 minutes of empiric antibiotic therapy is indicated, including therapy
incision time, administered every 4 hours during surgery, with agents having empiric activity against suspected
and continued for no more than 48 hours. In this case, the pathogens and able to safely achieve relevant CSF
patient has obesity disorder and weighs more than 120 concentrations. Cefepime and vancomycin are the most
kg; hence, the patient needs an initial dose of cefazolin appropriate options listed with consideration of CNS-
3 g (Answer C is correct). Given the patient’s weight, specific dosing (Answer D is correct). Ceftriaxone does
administering cefazolin 2 g initially is inappropriate not cover nosocomial-acquired gram negatives such
(Answers A and D are incorrect). Vancomycin is usually as Pseudomonas (Answers A and B are incorrect).
reserved for patients with a β-lactam allergy (Answer B Piperacillin/tazobactam would be reasonable according
is incorrect). to the spectrum of antibacterial activity; however, poor
CNS penetration of tazobactam limits the utility of this
2. Answer: C agent for meningitis and other CNS infections (Answer
Although critical care pharmacists may not officially C is incorrect).
be part of many antimicrobial stewardship teams, many
of their daily clinical activities constitute antimicrobial 4. Answer: A
stewardship activities. These may include selecting the The presence of the CTX-M gene detected on E. coli by
most appropriate treatment regimen and advocating rapid diagnostic testing usually signifies the presence of
the early de-escalation of antimicrobials. Even in the ESBL. This may be why the patient has not yet responded
presence of a formalized antimicrobial stewardship to piperacillin/tazobactam. The most appropriate action
team, these activities are often complementary to the at this point is to broaden the coverage to cover for
formalized activities of the team (Answer C is correct). potential ESBL-producing E. coli. Carbapenems remain
Given the wide variations in clinical practice, it may the drug of choice for ESBL-producing organisms,
not be feasible to include an infectious diseases–trained particularly in a patient who is hemodynamically unstable
pharmacist with every stewardship team. In that case, the (Answer A is correct). Extended-spectrum β-lactamases
activities and involvement of a critical care pharmacist are usually encoded on genes that carry resistance
may be even more crucial (Answer A is incorrect). The against other classes of antimicrobials; hence, resistance
goal of an antimicrobial stewardship team is to optimize to other antimicrobials is common; therefore, adding
therapy through selecting the most appropriate therapy either aminoglycosides or fluoroquinolones may not be
that would minimize adverse effects and unwanted appropriate (Answers B and D are incorrect). Although at
selection of resistant or opportunistic infections. times ESBLs may be covered by cefepime, that must be
Although decreases in antimicrobial expenditures determined by final AST (Answer C is incorrect).
commonly occur, this is not the main goal of the
team (Answer B is incorrect). Studies have shown that 5. Answer: C
antimicrobial stewardship efforts in critically ill patients E. cloacae is an AmpC β-lactamase–producing
do not worsen outcomes. Given the aggressive empiric Enterobacteriaceae. The use of ceftriaxone or extended-
antimicrobial regimens commonly used in critically ill spectrum penicillins (e.g., piperacillin and ticarcillin)
patients, antimicrobial stewardship should be instituted may select out de-repressed mutants, which are capable
to minimize adverse effects and the emergence of of causing the hyperproduction of AmpC β-lactamases.
resistance (Answer D is incorrect). De-repressed mutants are capable of producing resistance
against third-generation cephalosporins, monobactams,
3. Answer: D and extended-spectrum penicillins. In this case, the
This patient presents with a health care–associated patient was taking 10 days of ceftriaxone before a
CNS infection, given the post-neurosurgical and device- new blood culture was growing lactose-positive gram-
related etiology of the infection. The most common negative bacilli. Because lactose-positive gram-negative
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bacilli are usually Enterobacteriaceae, growing trimethoprim/sulfamethoxazole, but because this patient
multidrug-resistant pathogens such as P. aeruginosa has a sulfa allergy, this is not an option (Answer A is
and A. baumannii is less likely. Hence, the most likely incorrect). According to the HIV OI guideline, the
resistance mechanism in this patient is either selection second-line agent for the treatment of severe PJP is
of de-repressed mutants or acquisition of a pathogen intravenous pentamidine. Because the patient had severe
with ESBL. Both of these resistance mechanisms are hypoxemia, adjunctive steroids should be administered
adequately treated by a carbapenem. Hence, changing (Answer B is correct). Atovaquone and primaquine/
to a carbapenem pending final sensitivities is the most clindamycin regimens are usually reserved for patients
reasonable option (Answer C is correct). Both types with milder PJP. Furthermore, primaquine should not
of resistance mechanisms are capable of producing be administered to someone with a glucose-6-phosphate
resistance against ceftazidime and piperacillin/ dehydrogenase deficiency (Answers C and D are
tazobactam (Answers A and B are incorrect). Because incorrect).
the patient developed a new bacteremia while taking
ceftriaxone, it is not reasonable to continue ceftriaxone 8. Answer: B
alone (Answer D is incorrect). This patient has febrile neutropenia with no recovery of
neutrophils. According to the IDSA febrile neutropenia
6. Answer: B guidelines, when a source of infection is identified,
The patient is only on day 4 of therapy from proven the empiric antimicrobial therapy can be de-escalated
MRSA pneumonia. However, the patient developed to a more narrow-spectrum regimen according to the
a bacteremia with gram-positive cocci in pairs and antibiotic susceptibility report. In this case, because
chains despite receiving systemic vancomycin therapy. the E. coli was pan-sensitive, it would be appropriate
The most likely culprit is a vancomycin-resistant to de-escalate to a narrow-spectrum antimicrobial. The
Enterococcus sp. The medical team has already guidelines also specify that antimicrobial therapies
discontinued vancomycin; therefore, the new therapy should be continued for at least 14 days and until
must cover both the MRSA pneumonia and the neutrophils are greater than 500 cells/mm3 (Answer B
possibility of a vancomycin-resistant Enterococcus sp. is correct). Although the patient continues to be febrile,
Linezolid has good lung penetration and can adequately an otherwise stable patient with continued fevers rarely
cover vancomycin-resistant enterococci (Answer B is requires additional antimicrobial therapy according to
correct). Daptomycin would provide adequate coverage the guidelines. Hence, continuing more broad-spectrum
for vancomycin-resistant enterococci, but because it is therapy than necessary or adding other antimicrobials is
inactivated by lung surfactants, it is not a good option unwarranted (Answers A, C, and D are incorrect).
for the treatment of MRSA pneumonia (Answer A is
incorrect). Ceftaroline covers MRSA and has good
lung penetration; however, it covers only vancomycin-
resistant E. faecalis, not E. faecium. Because, at this
point, the speciation of the gram-positive cocci in pairs
and chains is not available, ceftaroline is not the best
choice (Answer C is incorrect). Tigecycline does cover
MRSA and vancomycin-resistant enterococci; however,
given its large volume of distribution and relatively low
serum concentrations, it may not be the ideal choice for
the treatment of bacteremia when other treatments are
available (Answer D is incorrect).
7. Answer: B
The patient’s history and clinical presentation suggest
PJP. It is severe enough to warrant intubation, and
the patient has a significant alveolar-arterial oxygen
gradient. The usual drug of choice for such patients is
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What are the learning objectives covered in the document?

What are the learning objectives covered in the document?

What are some of the common antimicrobial stewardship strategies mentioned?

What are some of the common antimicrobial stewardship strategies mentioned?

Infectious Diseases II

Seth R. Bauer, Pharm.D., FCCM, BCCCP, BCPS

Learning Objectives LOS Length of stay

2. Which statement best describes antimicrobial stew- A. Change piperacillin/tazobactam to cefepime.

8. A 50-year-old woman with acute myeloid leukemia

I. QUALITY IMPROVEMENTS – AMERICAN COLLEGE OF SURGEONS NATIONAL SURGICAL

B. Prevention of SSIs – ACS NSQIP and SCIP Measures

4. Prevention strategies: Pharmacy-specific

Table 1. Prophylactic Antibiotic Regimens for Surgery

Table 1. Prophylactic Antibiotic Regimens for Surgery (continued)

C. Prevention of Catheter-Associated Urinary Tract Infections (CAUTIs) – ACS NSQIP Measures

Was catheter removed

At least 1 of the following signs and symptoms Not a CAUTI

Not a CAUTI • Positive urine culture > 105 Not a CAUTI

Figure 1. Diagnosis of catheter-associated urinary tract infection according to CDC criteria.

D. Prevention of Catheter-Related Bloodstream Infections – ACS NSQIP

d. Antimicrobial/silver-impregnated catheter should be considered in patients with an anticipated

II. BACTERIAL MENINGITIS

b. Cell count and fluid analysis

D. Management and Treatment

Table 4. Selected Antibiotic CSF Penetration and Dosages for Meningitis

III. ANTIMICROBIAL STEWARDSHIP

D. Two Strategies, Which Could Be Used Synergistically Together

E. Effective Antimicrobial Stewardship Programs Can Be Financially Self-Supporting

F. Evidence Supporting Antimicrobial Stewardship Efforts in Critically Ill Patients

IV. RAPID DIAGNOSTIC TESTS

B. Early Pathogen Identification from Positive Bloodstream Cultures

10. Nanoparticles: Verigene blood culture test

C. Early C. difficile Identification

D. Early Identification of Fungal Organisms

3. Biopsies are often not feasible in critically ill patients.

Patient with signs and symptoms of infection

Initiate appropriate empiric antimicrobial therapy and draw initial PCT

Day 3 of empiric ABX

Confirmed diagnosis of Overall, clinical suspicion for

Draw PCT and use results to

Figure 2. Sample procalcitonin-guided antimicrobial management algorithm.

V. INTERPRETING SUSCEPTIBILITY REPORTS

B. Methods for Antimicrobial Susceptibility Testing (AST)

Table 7. Changes to CLSI Enterobacteriaceae Breakpoints with 2010 Updates

Figure 3. Sample microbiology confirmatory tests for specific resistance mechanisms.

E. Clinical Application of Interpreting AST

VI. MECHANISMS OF ANTIBACTERIAL RESISTANCE AND TREATMENT OF MULTIDRUG-

Table 8. Recent Resistance Rates in Hospital-Acquired Infection (2009–2010)

Table 9. Common Resistance Mechanisms

B. Mechanisms of Resistance (bacteria often possess several mechanisms)

C. Factors Associated with Resistance Acquisition

D. Clinical Approach to Common Pathogen Resistance Seen in Critically Ill Patients

d. Genetic mutation leading to sustained high-level production is possible (de-repressed mutants).

(C) PD targets similar to those of colistin

c. Ceftolozane/tazobactam is a novel β-lactam/β-lactamase inhibitor antimicrobial with enhanced

VII. IMMUNOCOMPROMISED PATIENTS

B. Solid Organ Transplantation

Figure 4. Usual sequence of infections after organ transplantation.a

VIII. HUMAN IMMUNODEFICIENCY VIRUS/ACQUIRED IMMUNE DEFICIENCY SYNDROME IN