critical Care

Antimicrobial Therapy in the Intensive Care Unit

MS Krishna Sarin*, M Vadivelan**, Chanaveerappa Bammigatti**

Abstract
Severe sepsis and septic shock in the intensive care unit (ICU) needs emergent coverage with empirical broad-spectrum
antibiotics, with a commitment to de-escalation once the organism and its susceptibility to a particular antibiotic becomes
known. The dose and duration of antibiotic must be optimized according to standard guidelines to prevent emergence of
resistant pathogens. Strategies of using Procalcitonin measurements in guiding the duration of antibiotic treatment and
aerosolized antibiotics are helpful in optimizing antibiotic usage. Efforts are needed to prevent emergence of antibiotic
resistance by pathogens, as the antibiotic pipeline is dwindling and the number of newly discovered multidrug-resistant (MDR)
pathogens is increasing. Prevention of infection must be given top priority by strict adherence to asepsis measures.

Keywords: Septic shock, intensive care unit, procalcitonin, aerosolized antibiotics, multidrug-resistant pathogens

he intensive care unit (ICU) is a place where

patients with complex medical problems are
crowded into a small area. The acute nature
of critically ill patients necessitates the use of broadspectrum antibiotics frequently.

Fever in a patient in the ICU must be considered

significant when the body temperature is >38.3C
(101F) and a detailed evaluation must be carried out to
ascertain whether infection is present or not.1 A lower
threshold of fever must be used in immunocompromised
patients.
However, as many as 50% of ICU patients with
fever have no apparent infection. Fever is a sign of
inflammation, not infection. Hence, noninfectious
causes of fever must be ruled out before subjecting
the patient to a number of costly and invasive
diagnostic procedures.
Noninfectious causes of fever in ICU

Postoperative fever: Fever on the first day following

major surgery is reported in 15-40% of patients.2

*Junior Resident
**Assistant Professor, Dept. of Medicine
Jawaharlal Institute of Post Graduate Medical Education
and Research (JIPMER), Pondicherry
Address for correspondence
Dr M Vadivelan
Q.No.: E-2, JIPMER Quarters, JIPMER Campus, Dhanvantari Nagar
Pondicherry - 605 006
E-mail: mevadivelan@hotmail.com

Procedures: Hemodialysis, bronchoscopy, blood

transfusions.

Endocrine disorders: Thyrotoxicosis, adrenal crisis.

Myocardial infarction, stroke and venous thromboembolism.

Drug fever: Common offending drugs are

cephalosporins, penicillins and amphotericin B and
phenytoin.

Infectious causes of fever in ICU

Sinusitis
Catheter-related bloodstream infection (CRBSI)
Ventilator-associated pneumonia (VAP)
Catheter-associated urinary tract infection (UTI)
Wound infections
Sepsis without an Obvious Focus
In critically ill patients, the source of infection may
not be apparent at the time of admission to the ICU.
In such patients, empirical antibiotics must be started
intravenously as early as possible within the first
hour of recognition of severe sepsis and septic shock.
Each hour of delay will decrease the survival by 7.6%
approximately.3
A rough guide to the choice of empirical antibiotics
when the focus of infection is unknown is presented
in Table 1.4
Empirical
coverage
for
methicillin-resistant
Staphylococcus aureus (MRSA) with vancomycin is
required in the following situations:

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Table 1. Empirical Therapy for Severe Sepsis with no
Obvious Focus
Clinical condition

Antimicrobial regimens (IV therapy)

Immunocompetent
adult

Piperacillin-Tazobactam/Meropenem/
Cefepime Vancomycin

Neutropenia
Piperacillin-Tazobactam/Meropenem/
(<500 neutrophils/l) Cefepime + Aminoglycoside
Vancomycin
Splenectomy

Cefotaxime/Ceftriaxone

IV drug user

Vancomycin

Subsequently, renal-modified dose of the drug can be

given.
Sepsis with an Identified Focus of
Infection

Ventilator-associated Pneumonia
The diagnosis of VAP is made on the basis of a new
infiltrate in the chest X-ray with two of the following:

Fever

Leukocytosis
Purulent tracheal secretions

Patients with indwelling vascular catheters

If patient has received quinolone prophylaxis

VAP can be classified as:

If the institution has a high incidence of MRSA

infections.

Early: If infection began within five days after

hospital admission.

If there is a high prevalence of MRSA isolates in

the community.

Late: If infection began more than five days after

admission.

Indications for empirical antifungal drugs are:

If the septic patient has been neutropenic for five

days or more

If the patient has had a long-term central venous

catheter

If the patient has been hospitalized in an ICU and

received broad-spectrum antibiotics for a prolonged
period.

Amphotericin B is the drug of choice for all lifethreatening fungal infections and as empirical
therapy in neutropenic patients with persistent fever.
Fluconazole is used for treatment of candidiasis in
patients who are hemodynamically stable and are
not immunocompromised. The echinocandins (e.g.
caspofungin) can be used for invasive candidiasis as
the drug provides improved coverage against all
Candida species.
A combination of antibiotics is usually chosen for
neutropenic sepsis and in patients with suspected
Pseudomonas infections. The drugs which can be
used in combination are ceftazidime or piperacillintazobactam or meropenem with an aminoglycoside.5
Indications for administering combination therapy
with two drugs active against Pseudomonas are:

Neutropenic fever

Severe sepsis and septic shock

Presence of serious infections like pneumonia,

endocarditis and meningitis.

All patients must receive the full loading dose of

each antimicrobial irrespective of the renal function.

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Indian Journal of Clinical Practice, Vol. 23, No. 10 March 2013

Empirical therapy for early VAP is recommended using

a single agent which can be any one of the following
drugs:6

Ceftriaxone

Levofloxacin/Ciprofloxacin/Moxifloxacin

Ampicillin + Sulbactam

Ertapenem

Combination therapy is advised for late VAP and when

VAP is suspected to be due to a multidrug-resistant
(MDR) pathogen.6 The drugs used are:

Ceftazidime/Cefepime

Imipenem/Meropenem

Piperacillin-Tazobactam + an Aminoglycoside/
Fluoroquinolone + Vancomycin/Linezolid.

Optimum duration of therapy for VAP is eight days.

Catheter-related Bloodstream Infections

The diagnosis of CRBSI depends on the demonstration,
by culture, of the same organism from the catheter
tip and blood culture. A colony count at least 3-fold
greater for blood obtained from the catheter hub
or a differential time to positivity (DTP) of at least
two hours at the catheter hub also indicates CRBSI.7
The catheter must be removed in severe sepsis,
suppurative thrombophlebitis, endocarditis and
infections due to S. aureus, Pseudomonas aeruginosa,
fungi or mycobacteria, and in a CRBSI that continues
despite 72 hours of antimicrobial therapy to which the
infecting microbes are susceptible.

critical Care
CRBSI is treated with the combination of a fourthgeneration cephalosporin/carbapenem plus vancomycin
to cover MRSA. An aminoglycoside is added if
Pseudomonas is suspected. The duration of therapy
depends on the infecting pathogen. Complicated
CRBSI (i.e., CRBSI-associated with suppurative
thrombophlebitis, endocarditis) requires at least
28 days of antibiotic therapy.

The recommended duration of antimicrobial

treatment for patients with catheter-associated UTI
who have rapid resolution of symptoms is 7 days and
10-14 days for those with a delayed response,
regardless of whether the patient remains catheterized
or not.8

Catheter-associated UTIs

Once the source of sepsis is known, the antimicrobial

therapy should be tailored according to the possible
infecting pathogens and their relative antibiotic
susceptibilities. A summary of the possible etiologic
agents according to the site of infection and the drug
that can be used is given in Table 2.9

Catheter-associated UTIs are diagnosed when

bacteriuria (10 colony forming units/ml) is associated
with symptoms compatible with UTI. Symptoms
include fever with rigors, flank pain, renal angle
tenderness, hematuria or pelvic discomfort.
These infections are often polymicrobial and are caused
by MDR pathogens. Urine culture results are required
to guide treatment. Catheter has to be replaced if it has
been in place for more than two weeks and if its use
cannot be discontinued.

Antibiotic Therapy Depending on the Site

of Infection

Treatment of Mdr Pathogens

MDR pathogens are a real and constant threat in
the ICU environment. The six most common MDR
pathogens encompassed in the eponymous ESKAPE

Table 2. Antibiotic Therapy Depending on the Site of Infection

Site of infection

Bacteria

Suggested treatment

UTI

E. coli

Ceftriaxone or Ceftazidime Aminoglycoside

Severe acute pyelonephritis

P. aeruginosa
Enterococcus species
Staphylococcus species

Intra-abdominal sepsis

E. coli

Ertapenem

P. aeruginosa

Piperacillin-Tazobactam

Enterococcus species

Third- or fourth-generation cephalosporin

(active against P. aeruginosa) + Metronidazole

Bacteroides species
Nosocomial pneumonia

Enterobacteriaceae
P. aeruginosa

-lactam (active against P. aeruginosa)

Aminoglycoside Glycopeptide (vancomycin)

S. aureus
S. pneumoniae
H. influenzae
Pneumonia without risk factors for MDR
Pseudomonas

S. aureus

Third-generation Cephalosporin Macrolide

S. pneumoniae
H. influenzae
Other gram-negative bacilli

Skin infections

CRBSI

Streptococcus species

-lactam + -lactamase inhibitor

Staphylococcus species

Piperacillin-Tazobactam

Gram-negative bacilli

Carbapenem

Staphylococcus species

Vancomycin + -lactam with activity against

P. aeruginosa

Enterobacteriaceae
P. aeruginosa

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group are Enterococcus faecium, S. aureus, Klebsiella
pneumoniae, Acinetobacter species, P. aeruginosa and
the Enterobacter species.
Tables 3 and 4 summarize the treatment options for
various MDR pathogens.
Newer Concepts in Antimicrobial Therapy

Procalcitonin as a Biomarker in Sepsis

Procalcitonin is the best studied biomarker for guiding
antibiotic treatment duration in the hospital setting.
Procalcitonin dynamics within 72 hours after onset of
sepsis may be correlated both with appropriateness
of the empirical antibiotic therapy and with overall
survival.10
Procalcitonin measurements integrated in clinical
algorithms have been shown to reduce the duration of
antibiotic courses by 25-65% in hospitalized and more
severely ill patients with CAP and sepsis.11

Pharmacokinetics in Drug-dosing Time/

Concentration-dependent Killing
Antibiotics like b-lactams, quinolones and vancomycin
exert their microbicidal activity depending on the
duration for which the plasma drug levels remain
above the minimum inhibitory concentration (MIC).
An appropriate strategy is to administer these
antibiotics as a continuous infusion rather than as bolus
doses.
On the other hand, aminoglycosides exert their action
depending on the peak levels achieved in plasma. So,
the appropriate strategy will be to give the entire daily
dose as a single bolus injection.
The pharmacokinetics of antibiotics is modified in ICU
patients owing to the large daily fluid balance, acute
changes in body weight, hypoalbuminemia, edema
and low hematocrit values that lead to a marked
change in elimination half-life, volume of distribution
and clearance. Sepsis increases capillary permeability

Table 3. Treatment Options for Resistant Gram-positive Bacteria

Drug

Route of
Activity against MRSA
administration

Activity against resistant

S. pneumoniae

Activity against vancomycinresistant Enterococci

Vancomycin

IV only

Yes

Yes

No

Daptomycin

IV only

Skin infection/Bloodstream infection

No

Yes

Linezolid

IV or oral

Pneumonia/Skin infection

No

Yes

Yes

No

Yes, against E. faecium

Quinupristin- IV only
Dalfupristin
Telavancin

IV only

Skin infection/Pneumonia

Yes

Yes

Tigecycline

IV only

Pneumonia/Skin infection

Yes

Yes

Ceftaroline

IV only

Pneumonia/Skin infection

Yes

No

Table 4. Treatment Options for Resistant Gram-negative Bacteria

Organism
Empirical therapy
Monomicrobial infection

Polymicrobial infection

Directed therapy
ESBL-producing Enterobacteriaceae

Carbapenemase-producing
Enterobacteriaceae
MDR P. aeruginosa

606

First-line therapy

Second-line therapy

Carbapenem

Piperacillin-Tazobactam

Tigecycline (not in UTIs)

Antipseudomonal agent
Carbapenem + Vancomycin

Colistin

Tigecycline (not in UTIs)

Antipseudomonal agent

Colistin + Vancomycin

Carbapenem

Tigecycline (not in UTIs)

Piperacillin-Tazobactam

Fluoroquinolone

Tigecycline

Colistin
Fosfomycin (parenteral formulation)

Colistin
Meropenem

Colistin

Indian Journal of Clinical Practice, Vol. 23, No. 10 March 2013

Piperacillin-Tazobactam + Vancomycin

critical Care
with third space sequestration resulting in higher
antibacterial drug clearances.

Table 5. Practices Promoting the Optimization of

Antimicrobial Use in the ICU Setting

Multiple organ dysfunctions cause a decrease in

antibacterial drug clearance. Hence, monitoring of
plasma drug concentrations needs to be performed
whenever possible because these concentrations are
difficult to predict in critically ill patients.

Provide adequate initial treatment of serious infections (e.g.,

pneumonia, bloodstream infections)

Aerosolized Antibiotics
Intermittent aerosolization of antibiotics into the
respiratory tract has been used in patients with
P. aeruginosa pneumonia, particularly in the setting
of cystic fibrosis. Tobramycin and colistin have been
used in pneumonia caused by MDR Pseudomonas.
Recently, amikacin, nebulized with special devices has
been used for MDR gram-negative pneumonia that was
unresponsive to standard therapy.
Antimicrobial Resistance and Its
Implications
MDR pathogens are most frequently encountered in
the ICU. The prime reason for the development of
antimicrobial resistance is antibiotic misuse. Irrational
antibiotic prescription for nondocumented infections
in stable patients, prolonged use of broad-spectrum
antibiotics without de-escalation, incorrect dosages
and dosing intervals and continuation of the antibiotic
course beyond the optimally recommended duration
contribute to the development of resistance. Practices
that promote optimization of antibiotic use in the ICU
are summarized in Table 5.12

Awareness of predominant disease causing pathogens

Up-to-date ICU-specific pathogen antibiograms
Drainage of abscesses, empyema cavities, other infected fluid
collections
Removal of infected foreign bodies (e.g. central venous
catheters)
Monitor serum drug concentrations when appropriate to
achieve therapeutic levels
Avoid prolonged courses of empiric antibiotic therapy
Consider de-escalation of antibiotics based on available
microbiologic data and clinical course
Use narrow-spectrum antibiotics when supported by clinical
situation and culture data
Establish appropriate thresholds for prescribing antibiotics
Develop predetermined criteria for the discontinuation of
antimicrobial therapy

Table 6. Predetermined duration of Antibiotic Therapy

based on the IDSA Guidelines
Site of infection

Duration of
antibiotic
therapy (days)

Lung infection
CAP due to S. pneumoniae

VAP

VAP and immunodepression

14

Pneumonia due to Legionella pneumophila

21

The key point is to avoid antibiotic misuse by using

them only in patients with documented infections
except if the infections are life-threatening and
avoiding the treatment of asymptomatic colonization.
De-escalation of broad-spectrum antibiotics based on
clinical response and microbiological findings is needed
to avoid the emergence of MDR pathogens.

Pneumonia with lung necrosis

28

Optimizing the duration of antimicrobial therapy

by following a protocol-guided discontinuation if
appropriate cultures are negative after Day 3 and
prescribing the antibiotic course for the optimum
duration will help to reduce the emergence of
resistance. The optimum duration of antibiotic therapy
for the commonly encountered infections in the
ICU, according to the Infectious Diseases Society of
America (IDSA) guidelines is given in Table 6. Certain
practices may be helpful in controlling antibiotic
resistance.

Postoperative meningitis due to

S. epidermidis or Enterobacteriaceae

14

Meningitis due to Listeria monocytogenes

21

Postoperative meningitis due to S. aureus

or P. aeruginosa

21

Brain abscess

28

Intra-abdominal infections
Community peritonitis

<8

Postoperative peritonitis

14

CNS infections
Meningococcemia
Meningitis due to S. pneumoniae

5-8
10-14

Catheter-related bacteremia
S. epidermidis or Enterobacteriaceae

<8

S. aureus/Candida species (uncomplicated)

14

S. aureus (complicated)

28

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Scheduled Changes in Antibiotic Therapy
Periodic changes in the antibiotic preference in treating
infections caused by the same pathogen (e.g., gramnegative infections treated with a cephalosporin for
the first six months and a fluoroquinolone for the next
6 months) may help to reduce the emergence of
resistance to either class.

Give sedation vacation and assess readiness to

extubate daily.

Use peptic ulcer disease prophylaxis.

Use deep-vein thrombosis prophylaxis (unless

contraindicated).

Prevention of UTIs

Antibiotic Class Cycling

A class of antibiotic is withdrawn from use for a

defined time period and reintroduced at a later point
of time in an attempt to limit bacterial resistance to the
antimicrobial agent.

Place bladder catheters only when absolutely

needed (e.g. to relieve obstruction), not solely for
the providers convenience.

Use aseptic technique for catheter insertion and

urinary tract instrumentation.

Minimize manipulation or opening of drainage

systems.

Ask daily: Is the catheter needed? Remove catheter

if not needed.

For any ICU, written protocols must be developed

based on the local ecology of microorganisms and their
pattern of resistance. This is best done in consultation
with the Dept. of Microbiology. An infectious
disease specialist consultation helps in improving
the accuracy of the prescription of antimicrobial drugs.
Prevention of Infections in the ICU
Simple measures to prevent infection and pathogen
cross-transmission assume significance considering the
huge expenses incurred in terms of patient morbidity
and mortality as well as the indirect costs involved
in treating a resistant infection. A summary of the
recommendations made by the Centers for Disease
Control is given below:13

Prevention of Central Venous Catheter

Infections

Educate personnel about catheter insertion and care.

Use chlorhexidine to prepare the insertion site.

Use maximal barrier precautions during catheter

insertion.

Consolidate insertion supplies (e.g., in an insertion

kit or cart)

Use a checklist to enhance adherence to the bundle.

Empower nurses to halt insertion if asepsis is

breached.

Cleanse patients daily with chlorhexidine.

Ask daily: Is the catheter needed? Remove catheter

if not needed or used.

Prevention of VAP

Elevate head end of bed to 30-45.

Decontaminate
chlorhexidine.

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oropharynx

regularly

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Prevention of Surgical-site Infections

Choose a surgeon wisely.

Administer prophylactic antibiotics within

one hour before surgery; discontinue within
24 hours.

Limit any hair removal to the time of surgery; use

clippers or do not remove hair at all.

Prepare surgical site with chlorhexidine-alcohol.

Maintain normal perioperative blood glucose levels

(cardiac surgery patients).

Maintain perioperative normothermia (colorectal

surgery patients).

Prevention of Pathogen Cross-transmission

Cleanse hands with alcohol hand rub before and
after all contacts with patients or their environments.
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Amyloid Imaging Guideline Issued

Use of new, FDA-approved imaging technologies for beta-amyloid protein plaques in the brain should be
limited to a relatively small subset of individuals, according to a new guideline issued jointly by the Alzheimer's
Association and the Society for Nuclear Medicine and Molecular Imaging. According to the statement, PET
scans with florbetapir (Amyvid) or other tracers now in the development pipeline are appropriate only for three
patient presentations

Persistent or progressive and unexplained mild cognitive impairment

Clinical diagnosis of possible Alzheimer's disease because of an atypical clinical course or an etiologically
mixed presentation

Progressive dementia beginning at age 65 or younger. (Source: Medpage Today)

Breakthrough: First Digital Atlas of Brain

Understanding the most complex human organ - the brain, has now become a lot simpler. In a major breakthrough,
scientists at Berkeley Lab has made it possible to get a front row view into how the brain develops and functions
and pinpoint which part of the organ is playing truant during neurological disorders like autism, epilepsy and
schizophrenia. The scientists have created the world's first genome-wide digital atlas of gene enhancers in the
brain - the switches that tell genes when and where they need to be switched on or off. This atlas completely
documents the cerebrum - the region that is of critical importance for cognition, motor functions and emotion
identifies and locates thousands of gene-regulating elements which are the underlying causes of neurological
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