Drug resistance of microbes has become a major challenge in treating ICU patients successfully. There are many factors that contribute to the development of drug resistance, including irrational antibiotic use, lack of antibiotic stewardship programs, and poor infection control practices. Implementing strict antibiotic policies, having responsive microbiology departments, and educating healthcare providers on following clinical guidelines are important first steps to prevent drug resistance. It is also essential to monitor antibiotic use, tailor therapies based on culture results, and withdraw antibiotics appropriately once infections have resolved. A multifaceted approach involving hospitals, healthcare workers, and communities is needed to curb the growing issue of antimicrobial resistance.

1. COMBATING DRUG RESISTANCE IN THE INTENSIVE
CARE UNIT (ICU)

2. Review Article
INTRODUCTION
The battle for supremacy between man and microbe
continues to play itself out in the ICU’s of this world.
Everyone has an opinion on what is to be done and what
should be done yet when it comes to putting it into practice
they still automatically do what they have been doing for
years. One should remember that effective anti- microbials
are developed tardily over many years but the
development of drug resistance can be brought about quite
rapidly. Research shows that the major faults for the
appearance of resistant microbes lies in many irrational
practices that can be addressed if there is a will to do so.
To understand the development of resistance the
difference between carriage of abnormal flora and their
overgrowth needs to be appreciated. Whereas carriage is
the persistence of abnormal flora in the throat or gut ,
overgrowth implies their presence in high concentrations
usually >105 colony forming units of PPM/mL of saliva or
per gram faeces. Overgrowth guarantees increased
spontaneous mutation leading to polyclonality and
antibiotic resistance. The patient then becomes a reservoir
of resistant organisms and at risk for endogenous
infections. Further overgrowth promotes dissemination
throughout the ICU. About 33% of patients develop de
novo resistance whereas another third acquire resistant
organisms following transmission via hands of health care
workers and the rest import the organisms in their
admission flora [1].
It should be made clear that healthy individuals do not
become sustained carriers of abnormal microorganisms. It
has been recently learnt that illness severity is the most
important risk factor for the carriage of abnormal often
COMBATING DRUG RESISTANCE IN THE INTENSIVE CARE UNIT (ICU)
Deepak Rosha
Senior Consultant, Department of Respiratory Medicine & Critical Care, Indraprastha Apollo Hospitals, Sarita Vihar,
New Delhi 110 076, India.
Drug resistance of microbes has become a major stumbling block to treating patients successfully in the ICU.
There is no doubt that microbes have the capacity to mutate or acquire drug destroying enzymes, but a
multitude of errors by health care providers plays a major role in facilitating the development of resistance. The
maintenance of drug use discipline in closed ICUs and having a responsive microbiology department are the
first steps towards prevention of microbe resistance. Having an infection control committee that is able to
collect and disseminate data is the next essential step. Education of health care providers to provide uniformity
of health care according to set guidelines is the culmination of this towards the goal of minimizing the
development of anti microbial resistance.
Key words: Drug resistance, ICU, Prevention of.
resistant microbes usually in the gut. Overgrowth is
promoted by the use of opiates, H2 blockers, proton pump
inhibitors and anti microbials [2].
CLOSED VS OPEN ICU
A major issue to be addressed is ICU policy and
discipline. An open ICU is one where all consultants treat
their patients according to their own beliefs and learning
and they have the power to overrule the intensivist who is
usually a secondary consultant and can only make
suggestions. In such a set up enforcing antibiotic policy
and introducing rational use of therapy becomes that much
more difficult.
In the closed ICU system however, the intensivist is in-
charge of all aspects of every case and will make all
decisions including antibiotic usage. In the latter set up it
becomes much easier to implement not only antibiotic but
other policies that may directly or indirectly affect
emergence of drug resistance [3].
INFECTIONS AND THE PATIENT
The microbiology of the patient changes as the length
of time in ICU increase [4]. Studies have shown that
(a) in the first seven days the microorganisms of patient
flora comprise Strep pneumonae, H influenza,
Moraxella catarrhalis, C albicans, Staph aureus, E
coli. These organism cause primary endogenous
infections including pneumonias in critically ill
patients.It may be noted that whether C albicans can
cause pneumonia at this stage is still under
investigation. The incidence of these endogenous
infections is 55%.
Apollo Medicine, Vol. 8, No. 1, March 2011 24

3. Review Article
25 Apollo Medicine, Vol. 8, No. 1, March 2011
(b) after seven days the microbes have changed and are
usually gram negative e.g. Klebseilla, Proteus,
Enterobacter, Morganella, Citrobacter, Serratia,
Citrobacter, Acinetobacter, Pseudomonas and
MRSA. Infections by these microbes are considered
to be secondary endogenous and occur 30% of the
time.
(c) a third category of infection without any time frame
is labeled exogenous and is attributed to poor
hygienic measures or introduced by devices. This
occurs 15% of the time and the organisms are usually
the GNB mentioned in (b) above.
It has been seen that while the patient is admitted for
the first seven days the organisms are usually sensitive to
third generation cephalosporins. Studies have shown
however that if the patient is given prophylactic 3rd
generation cephalosporins, resistant GNB and sometimes
MRSA colonise the patient. Further studies have shown
that selective decontamination of gut by oral Polymyxin b,
Tobramycin and Vancomycin can prevent the emergence
of these resistant bacteria. However as of now these
measures have not found universal consensus outside a
few centres in Europe [5].
Microbiology department
The microbiology department has a pivotal role in
combating anti–microbial resistance. The patients with
severe infections in the ICU come from three sources i.e.
(a) community; (b) another hospital, and (c) same
hospital.
Furthermore some of these patients may be
immunocompromised. The role of microbiology starts
once an infection has been identified. The source as well
as the site should be documented. The organisms are
identified and the drug sensitivity communicated to the
treating physician. The department should normally
publish a monthly in-house circular that shows the
common microbes isolated from the identified sites and
the resistance pattern. The department should also
immediately communicate if a drug resistant microbe has
been isolated to the administration to take necessary
measures to prevent the spread to other patients .In
addition the department should be doing surveillance
cultures from the throat and gut of potentially infected
patients [6].
Antibiotic policy
The antibiotic policy of the hospital is formulated by
the infection control committee that includes the
microbiologist, intensivist, nursing and medical adminis-
trators. and infectious disease specialist [7]. The policy
should clearly spell out
(a) Initial antibiotic regimens to be used in seriously ill
patients according to the immune status, length of
hospital stay, procedures done and site of infection of
the patient .In the ideal situation antibiotics should
only be used where infection exists, however in
patients with systemic inflammatory response due to
non infectious causes it may be impossible to rule out
sepsis. In such a situation antimicrobials with broad
spectrum are required to be used. Antibiotic policy
will create uniformity and remove irrationality from
such situations. Further the isolation of organisms
low virulence should not justify the initiation of
antimicrobial therapy. In cases of fever of unknown
origin and in the absence SIRS it may be sufficient to
remove indwelling catheters. Prophylactic
antibiotics should be used for a short period of time
[8].
(b) Samples should be obtained from blood, trachea or
sputum, urine or any other infected site before
starting antibiotics. Where the patient is already on
antibiotics it may be prudent to wait 48hrs for a
response before obtaining fresh cultures. In such
situations cultures should be obtained before the next
therapeutic dose of antibiotic is due .
(c) Antibiotic combinations which are considered
irrational or detrimental to the treatment should be
conveyed to the treating physicians. Protocols should
be developed for specific infection and there should
be specific recommendations for first and second
line drugs and combinations to be used. This should
be according to the most common organisms causing
infection for that site in the region. The therapeutic
dosing, drug interactions and adverse reactions
should be monitored. It should be remembered that
adverse events such as nephrotoxicity, ototoxicity,
and selection of resistant mutants are related to
inadequate concentrations of antibiotics. There is
usually an increase in body mass distribution in the
critically ill. Haemodynamic instability and renal
failure also affect drug elimination. Hence wherever
possible plasma drug concentrations especially
where the therapeutic window is small should be
performed [9].
(d) Information from the laboratory should be passed on
as quickly as results are known to reduce the time
that broad spectrum antibiotics are used.
(e) Antibiotic tailoring to specific antibiotics once

4. Review Article
Apollo Medicine, Vol. 8, No. 1, March 2011 26
organism and sensitivity has been identified or de
escalation therapy is an essential strategy to prevent
the appearance of resistant organisms. As far as
possible once an organism and sensitivity are known,
mono therapy should be used. However where there
is high incidence of treatment failure or chance of
emergence of resistance the use of two or more
antimicrobials is recommended [10].
(f) Antibiotic withdrawal policy once infection has been
controlled and length of time antibiotics to be used
should be rationalised. The first evaluation of
therapeutic response should be 72hrs after starting
empiric treatment. This may be earlier if the clinical
response is unsatisfactory with further worsening of
the patient’s condition. It is necessary to ensure that
the anti microbials have good penetration into the
affected tissue and are given at appropriate intervals
to guarantee an adequate pk/pd relationship.
Antibiotics are usually continued for 72 hrs after
symptoms of fever, leucocytosis, haemodynamic
instability and pulmonary shunting have subsided. In
patients infected with multi drug resistant organisms
the treatment may be prolonged to 14 days [11].
(g) Antibiotic cycling is an important strategy found to
be effective in limiting the emergence of resistance.
This consists of periodic substitution of one class of
antibiotics for another or a combination having a
similar spectrum of activity but not sharing the same
mechanism for the development of resistance.
During each period or cycle of a few months duration
only antibiotics corresponding to that cycle may be
used [13].
(h) Reserve antibiotic list where some antibiotics use is
restricted should be made. In the situation of open
ICUs it becomes important that some antibiotics are
to be only used in special situations. This preserves
the spectrum of activity of these reserve antibiotics.
(i) Preemptive therapy policy consists of administering
antimicrobials before the appearance of clinical
signs of infection. This concept was developed in
haematological patients using serological tests
which allows the diagnosis of infection before the
appearance of clinical signs. Such patients are at a
high risk for mortality especially from candidemia
[14].
(j) Policy for antifungals agents and their empiric, pre
emptive as well as prophylactic use are required.
(k) Policy for selective decontamination of gut has been
mentioned above. Studies from Europe have found
this to be highly effective in limiting drug resistance
but the procedure is not yet universally accepted.
(l) Systems for monitoring implementation and
enforcement should be in place. All monitoring
systems should never have a punitive but rather a
corrective and educative approach.
MEASURES IN ICU
The ICU remains the home of super bugs resistant to
many of the major antibiotic groups. The ICU measures
for emergence of drug resistance are firstly preventive
which include policy measures set out above [15]. In
addition the change of lines and catheters at regulated
intervals and their early removal are very important. The
ICU staff should daily mark the number of days of lines,
catheters and antibiotics have been used. The early use of
enteral feeding as apposed to parenteral feeding has a
salutary effect on recovery from infection [16]. The
prolonged and indiscriminate use of proton pump
inhibitors predisposes the patient to lung infections. A
single nurse for every patient is a very important measure
and tends to curb the spread of organisms. Hand washing
remains a corner stone of prevention of spread of resistant
organisms.Along term ICU facility for those patients who
are in a vegetative state is an expensive but necessary
measure as these patients become reservoirs of resistant
organisms. The secondary measures are required when
resistant microbes have been isolated from the patient.
Placing the patient in an isolation facility with negative
pressure, dedicated nursing staff, hand washing of
attending doctors as well as gowns and mask become
necessary [10]. Some measures for prevention of
ventilator associated pneumonia have been found to be
effective. These include keeping the patient at least 30
degrees upright as well as sub-glottic aspiration of the
endotracheal tube or tracheostomy tube. On the other hand
the use of silver impregnated endotracheal tubes and line
catheters as well as antibiotic coated catheters have not
reduced late onset VAP or blood stream infections
respectively. Finally every instance of significant ICU
fever should result in a thorough search for the cause in
which blood counts, blood, urine, tracheal cultures and
chest xrays as well as sonographic evaluation of abdomen
is to be considered [17].
MEASURES IN THE COMMUNITY
It is very necessary to involve the general practioners
in this fight to control drug resistance. The indiscriminate
and irrational use of antibiotics sets the stage for the
development of resistant and virulent organisms in the
society itself. If possible the use of some higher antibiotics

5. Review Article
27 Apollo Medicine, Vol. 8, No. 1, March 2011
8. Heininger A, Meyer E, Schwab F, et al. Effects of long
term routine use of selective digestive decontamination
on antimicrobial resistance. Intenvive care med
2006,32:569-676.
9. Burke JP. Infection control. A problem for patient safety. N
Engl J Med, 2003, 348: 651.
10. Rosenthal VD, Maki DG, Salomao R. Device associated
nosocomial infections in 55 intensive care uniys of 8
developing countries. Ann Intern med 2006, 145(8): 582-
589.
11. Stone PW, Hedblom EC, Murphy DM, et al. The
economic impact of infection control:Making the
business case for increased infection control resources.
Am J infect control 2005,33(9):542-547.
12. Dodek P, Keenan S, Cook D, et al. Evidence based
clinical practice guidelines for the prevention of VAP. Ann
Intern med 2004,141: 305-313.
13. Drakulovic MB, Torres A, Bauer TT, et al. Supine body
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mechanically ventilated patients: A randomized trial.
Lancet1999, 354 (9193):1851-1858.
14. American Thoracic Society, Infectious Disease Society of
America, Guidelines for the management of adults with
hospital acquired, ventilator associated, and health care
associated pneumonia. Am J Respir Crit care med,
2005,171: 388-416.
15. American College of chest physicians and society of
Critical care medicine Consensus conference
committee, Definitions for sepsis and organ failure and
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16. Neuhauser MM, Weinstein RA, Rydman R, et al.
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should be restricted to hospital only, or only allowed in
culture proved cases outside the hospital. This of course
requires responsible behaviour from physicians and
enforcement of laws by government. Education of the
community, monitoring of over the counter drugs
dispensation by chemists and monitoring of prescriptions
by medical council is also necessary.
CONCLUSION
A brief attempt has been made to outline the mammoth
task of controlling and combating drug resistance in the
ICU. It cannot be done by one individual but requires the
collective will of the whole community and hospitals to
combat this growing menace.
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