An Approach to Antibiotic Prescription in ICU

Our approach is:

1. Ask how well the patient is!

In the gravely ill patient (as opposed to the 'not-so-seriously ill'), there is
little time for delay, and an error in choice of antibiotics may well cost the
patient his/her life. Prolonged ventilation and prior antibiotic
use (especially of broad-spectrum agents) predispose to resistance.
2. Know the organism

Your benchmark for treatment should be treating a known organism with

an appropriate dose of antibiotic to which that organism is likely to
respond, based on sensitivity testing. This ideal will often not be met.
Sometimes you will obtain an organism and its sensitivity on routine
microbiological surveillance and then the patient will show features of
infection likely to be due to that organism. More often, you will have to
rely on empiric therapy. ( See also: [Am J Med 1991 301 165-72] )
3. Know the environment

Know the patterns of resistance, and the organisms prevalent in your ICU
environment. This helps with antibiotic choice.
4. Identify the site of infection

Positive blood cultures are simply not good enough. Identify the site of
infection (e.g. respiratory tract, urinary tract, a subdiaphragmatic
collection, or whatever) and address any surgically remediable pathology
right away. The primary treatment of an abscess, for example, is immediate
drainage, notantibiotics.
5. Don't overtreat

Never treat a "fever" or a "leukocytosis" with antibiotics. Assess the patient

as a whole, including their predisposition to infection, and likely sites of
infection. Ask whether the patient is sick enough to justify antibiotics,
rather than treating laboratory values! If you are going to start 'empiric'
therapy,first obtain microbiological specimens for culture. Document your
reasons for starting therapy, and choose as narrow an antibiotic spectrum
as you can reasonably 'get away with'. When you get the results of ID +
sensitivity testing, revise your treatment to 'narrow-down' the spectrum as
far as possible.

6. Don't delay

If the patient clearly needs treatment, treat. Do NOT wait for sensitivity
results - if the patient is ill and needs treatment now, sensitivity results will
make a very poor epitaph.
7. Don't undertreat

Even more important than giving adequate doses of an antimicrobial is not

to give an agent that has a substantial likelihood of failure . In a critically
ill patient , you won't get a second chance. If you have antibiotic X and
antibiotic Y, and in your unit there is a 35% incidence of resistance to X,
but 3% resistance to Y, it's clear which one you should use, even if Y costs
three times as much as X, and is regarded as a reserved agent !
8. Know how critical illness interacts with the antibiotic

The pharmacokinetics of antimicrobials is often substantially altered in the

critically ill.
9. In vitro response is not the same as in vivo

There are some agents that appear to be effective in vitro, but will not work
in vivo. Always look at sensitivity results in the light of your knowledge of
the microbe and the patient (and especially the site of infection!).
10. Don't treat for too long

We usually give antibiotics for too long. In our opinion there are very few
circumstances where very prolonged 'therapy' is desirable, although many
current recommendations for treatment of nosocomial pneumonia suggest
treatment be continued for two weeks, or even more. Without good
evidence either way, we think this is often far too long. If the patient has
responded dramatically, is clinically much improved, and leukocytosis and
fever has subsided for 24 to 48 hours, we think that cessation of antibiotic
therapy is a good idea. There are notable exceptions to this guideline infective endocarditis and deep-seated Staphylococcus aureus infections,
for example, must be treated for prolonged periods (at least 4 weeks with
deep-seated Staph. infection).
11. Establish treatment guidelines

Each unit should have antibiotic guidelines ('for the obedience of fools and
the guidance of wise men')!

12. Discuss your treatment with experts

Most microbiologists are very keen to advise you. Listen to them - they
usually know their subject far better than clinicians. (The Infectious
Diseases Society of America also recommends computer-based monitoring
with feedback , combined with the use of benchmarking data to tell you if
you're being silly (or good) in your antibiotic prescribing).
If you disagree with the above, and have constructive comments about how we can improve
this approach, email us! Please note that the information and ideas contained in this
document should not be used to guide clinical decision-making. If you are unsure about
what agent to use in clinical patient management, consult a human expert, not our webpage! We will not be held responsible for any consequences of your clinical management
decisions.

Quick Tables of Organisms, Sites and Treatment

The following tables are not meant to be definitive, and
should be read in conjunction with the above guidelines.
Organisms and their (tentative) treatment
(In the table 'Quinolone' always means a fluoroquinolone)
Organism
Acinetobacter
spp.

Rx if 'Naive'

Alternative

Rx if 'v. Resistant'

Avoid

Quinolone
OR cefepime
OR imipenem (? + aminoglycoside)
-lactam+inhibitor
eg. amoxycillin + (uncommon)
clavulanate

all
cephalosporins,
penicillin,
aminoglycosides

Bacteroides
fragilis

Metronidazole

Enterobacter

carbapenem
OR cefepime
OR (?) high dose -lactam+inhibitor

1st, 2nd, 3rd gen

cephalosporins

Enterococcus
faecalis

Vancomycin + aminoglycoside

quinolones,
cephalosporins,
ampicillin!

Ampicillin +
aminoglycoside

Enterococcus
faecium

Escherichia coli Quinolone

Vancomycin +
aminoglycoside
(unlessVRE)

quinolones,
cephalosporins,
E. faecium is
resistant to
carbapenems

Co-trimoxazole

Ampicillin, 3rd

lactam+inhibitor
gen
OR carbapenem
cephalosporins
OR cefepime
Klebsiella spp.
Organism
Proteus
mirabilis

Cefotaxime
Rx if 'Naive'
Quinolone OR
cotrimoxazole

Quinolone
lactam+inhibitor
OR ? Cefuroxime
OR carbapenem
+ aminoglycoside
OR cefepime
Alternative

Rx if 'v. Resistant'

? ampicillin
(resistance now
common)

3gen
Cephalosporin +
aminoglycoside
OR piperacillin +
tazobactam
3gen
Cephalosporin +
aminoglycoside
OR piperacillin +
tazobactam

Avoid

Proteus (other)

Quinolone

? 3rd gen.
cephalosporin

Pseudomonas
aeruginosa

Antipseudomonal
penicillin
(piperacillin,
mezlocillin,
azlocillin,
ticarcillin) ? +
aminoglycoside

Quinolone
Antipseudomonal
OR cefepime
cephalosporin (eg.
OR imipenem (?
ceftazidime) ? +
+
aminoglycoside
aminoglycoside)

NB. if piperacillin
resistant, adding
a-lactamase
inhibitor won't
help!

First-generation
cephalosporin (eg Vancomycin
cefazolin)

quinolones,
penicillin, 3rd gen
cephalosporins,
MRSA are
resistant to
imipenem

Staphylococcus
Cloxacillin
aureus

Staphylococci
- coagulase
negative (CNS,
S. epidermidis)

vancomycin (if pathogenic)

(rarely, the organism is sensitive to cloxacillin, 1st gen.
cephalosporins. Do NOT bank on this!)

Streptococcus
pneumoniae

Penicillin (2MU 4
hourly)

Organism

Rationale

Rx if 'Naive'

Macrolides
Alternative

Cefotaxime
(OR ceftriaxone most quinolones
OR vancomycin)
Rx if 'v. Resistant'

Avoid

Looking at antibiotic therapy in ICU from the point of view

of a perplexed physician, there seem to be two broad
schools of opinion among the "experts" in the field. We will
call these the:
1. Boring Old Standard Hypothesis (BOSH), to which I
still subscribe;
2. The "Thorough Elimination of Microbes Prevents
Trouble" theory (which we will call TEMPT).
Needless to say, the terms and abbreviations are entirely
my own! We will first explore BOSH, which I see as follows:
B.O.S.H.

"We are in the age of bacteria, which started about

3.5 billion years ago, and still shows no signs of ending.
Other non-bacterial organisms (which, from the bacterial
point of view, are merely nutrient-rich broth in a flimsy
package) have two choices:
1. Be eaten now; or
2. Find ways of co-operating with the bacteria, or at least
coexisting fairly amicably (Be eaten later).
Over the last several billion years, organisms have evolved
wonderfully complex ways of talking to bacteria, and
modulating their behaviour. Likewise, bacteria have evolved
wonderfully complex ways of talking to other organisms,
and modulating their behaviour, sometimes terminally. Such
signalling is exemplified by the recent insights we have
gained about bacterial and host interactions in the human
bowel. In other words, wherever there are bacteria, there is
a complex ecology.
One small component of this ecology is antibiotics.
Unfortunately, doctors (and vets & farmers) have seized
upon this one small component as if it were the Holy Grail.
They have, either for reasons of 'doing good' or for profit,
used this component enthusiastically and relentlessly, and

have consequently modified the ecology. Such modification

is not necessarily a good thing , especially as the major
modification has been a compensatory increase in the
variety and numbers of bacteria that find such antibiotics
inoffensive, or even occasionally, tasty!" [Me, 2001]
Physicians such as myself, who adhere to the BOSH school
of thought, advise caution in administering antibiotics, lest
one muddles up the ecology even further, especially in the
long term. Details of this approach will be explored later.
T.E.M.P.T

I think there is at least one other approach, which although

not perhaps widely acknowledged or admitted, is fairly
prevalent. This approach seems to me to be to "nail the
bugs before they do harm". Here are several examples of
the TEMPT approach:
The housewife who liberally sprays disinfectants on
every flat surface in her house, egged on by
innumerable television adverts about the evil germs
that are lurking in every corner, waiting to pounce.
The General Practitioner, who gives every kid with a
sore throat an antibiotic. This has almost become the
norm in many developed countries. There are two
subspecies of this G.P.
1. The endangered minimus subspecies, who,
believing that Strep. throats are a bad
thing, and others are probably not a big
issue, does a throat swab and gives
Penicillin;
2. The "kill all known germs dead"
subspecies, who (often following the
prompting of the most recent drug rep),
gives the most broad-spectrum antibiotic in
his armamentarium.

 The Surgeon, who gives prophylactic antibiotics just

before the knife cuts skin (with perhaps one further
dose intra-operatively, if the surgery will last longer
than the half-life of the antibiotic). Such an approach
has been shown to work well, and is fully justified. It is
a good thing .
The less well informed surgeon, who continues his
"prophylactic" antibiotics long after the operation has
ended, sometimes even for three or more days. We are
not aware of any significant study that justifies this
practice, and at present (from our narrow BOSH
perspective) regard this as a bad thing .
The up-to-date, literature-reading Surgeon who has
recently read up on management of acute pancreatitis,
and who, in substantial necrotising pancreatitis
involving a large part of the pancreas (perhaps 30+%)
will give prophylactic antibiotics which penetrate the
pancreas well (such as imipenem). We're not totally
convinced about this, but recent literature strongly
suggests that this is a good idea.
The keen young epidemiologist, who has read metaanalyses on "Selective Decontamination of the
Digestive Tract" (SDD) such as that in the BMJ [ British
Medical Journal 1998 16 1275-85, D'Amico et al],
which asserts that:
"This meta-analysis of 15 years of clinical
research suggests that antibiotic prophylaxis
with a combination of topical and systemic
drugs can reduce respiratory tract infections
and overall mortality in critically ill patients.
This effect is significant and worth while, and it
should be considered when practice guidelines
are defined".
Whew! Although we disagree with this
sweeping conclusion, we will defer comment.

It can be seen that the TEMPT approach is heterogeneous.

It also fulfills a deep psychological need in the attending
doctor, to "do something". Even die-hard adherents to the
BOSH approach (such as myself) have to admit that in some
circumstances, the TEMPT approach is entirely correct. In
others, we believe that it is totally wrong. The grey areas
are the interesting ones.

Infection in ICU
There is no doubt that infection is a major association of
ICU morbidity and mortality. There is also good evidence
that antibiotic resistance is widespread, and an enormous
problem. For example, the 1992 EPIC study, which looked at
point prevalence of infection and bacterial resistance
showed that 45% of 10 038 patients were infected (21% of
these infections presumably nosocomial), and that there
was widespread resistance of major pathogens to important
antibiotics. [EPIC was published in JAMA 1995 274 639-44;
For an overview, see Int. Care Med. 2000 26 S3-8, J-L
Vincent].
Of even more concern is the emergence of difficult-to-treat
(and sometimes, impossible-to-treat) pathogens such as
vancomycin-resistant
Enterococci,
and
multiresistant
strains of Pseudomonas aeruginosa and Acinetobacter spp.
Why is there increasing resistance?

It is intuitively obvious that in rapidly changing microbial

ecologies, selection pressure is necessary if an antibioticresistant bacterium is to achieve prominence. In other
words, an antibiotic that 'decreases the competition' must
be given, and if the bacterium is to remain prominent, an
antibiotic must be given repeatedly. This is a
necessary criterion for the emergence of resistance to
antimicrobials.
In order that a bacterium (resistant to an antimicrobial)
can attack a particular patient, there are several other
obvious requirements:

 The patient's defences should be "down", something

that is common in ICU, where patients are often
nutritionally compromised, with breaches in their
integument;
The microbe must gain access to the patient, usually
carried on the hands of the attending doctors or
nurses;
The microbe must establish a "foothold" (pilum-hold?)
on the patient, competing with endogenous patient
flora;
The microbe must invade the patient, and cause
disease.
Equally clearly, if any one of these steps or predisposing
states is removed, a bacterium or fungus will have a torrid
time in trying to attack the patient. We therefore have
several strategies we can employ in preventing such
onslaught. We can:
1. Wash our hands. This simple practice, first espoused
by Semmelweiss in the century before last, is still not
ahered to, even in ICUs that preach this gospel
(Semmelweiss was hounded to death by his
colleagues);
2. Ensure adequate patient nutrition. Another major
failing of medicine - a substantial proportion of
hospital patients (and especially, intensive care
patients) are either grossly nutritionally compromised,
or "at risk";
3. Minimise suppression of endogenous patient flora.
More of this later;
4. Minimise invasive (and often unnecessary) breaches in
the patient's integument, and where such breaches are
absolutely necessary, minimise their duration, and
manage them "aseptically" as far as is possible.

An important note in assessing studies

At this point we should pause to consider the implications of

the
above
obvious
measures.
We
have already
mentioned the enthusiastic meta-analytical admonition to
use antibiotics 'prophylactically' in ICU (SDD). Let's look at
this in more detail.
Any study that purports to be a meaningful evaluation of the
use of antibiotics in ICU, but that hasn't stuck to these
"rules" should be regarded with grave suspicion. For
example, let's say we have a high prevalence of infection in
ICU X, and we successfully decrease the infection rate by
whacking everyone on a new, expensive, "broad spectrum"
antibiotic, or combination of antibiotics. We might be
tempted to praise this antibiotic as the new wonder drug,
and rush around administering it willy-nilly to all of our
patients.
Not so. For the study will not tell us whether, in say two
years time, prevalent microbes will have emerged that have
high levels of resistance to our new wonder-drug. (We know
from past experience that this will likely be the case). The
study will almost certainly not have looked at the effect
introduction of the agent has on the ecology of the ICU, the
hospital, or even the community.
But even more important than these cautions is the
possibility that the same results (minus the expense and
risk of the antibiotics) may have been achieved by ensuring
adequate handwashing, as well as other lesser measures
such as limiting the dwell time of intravenous cannulae, and
optimising patient nutrition, all with no adverse effect on
microbial ecology, and other important beneficial effects!
There is another less obvious 'confounding variable' when it
comes to assessing such studies. Let's say that in the
general wards of a hospital, it is common practice to lash
out with antibiotics at the first sign of a temperature, white
cell count, or whatever. Let us also (for the sake of
argument) assume that such antibiotic therapy is often
'standardised' ("homogenous antibiotic prescribing") and

prolonged, suppressing the patient's normal flora, and

encouraging colonisation by resistant organisms. It's clear
that in such circumstances (but not of course
in our hospital, he cried!), patients who are admitted to ICU
will often be colonised by resistant organisms on admission,
and normal host flora will be suppressed, with their
'receptors' on the host occupied by harmful pathogens.
Such patients will be predisposed to aggressive infection. If
we now administer potent antibiotics early on to these
patients, we might in the short term see a decrease in
infection, leading us to believe that early, aggressive and
profligate antibiotic therapy in ICU is the right thing!

Patterns of Resistance in Specific Organisms

Escherichia coli
E. coli is a common hospital pathogen. -lactamases
are now almost the norm! Chromosomal -lactamases
(also called Type I) are common, but plasmid-mediated
-lactamases (notably ESBLs - extended spectrum beta
lactamases) are also widespread. ESBL spread is
thought to be related to excessive use of latergeneration cephalosporins, now being further
promoted by use of quinolones (and co-trimoxazole).
The spread of ESBLs is made worse by their common
association (on the same plasmid) with multiple other
resistance genes. Many laboratories are unreliable in
reporting the presence of ESBLS. If E coli is reported
as resistant to ceftazidime or the MIC is 2 or more, you
should assume the organism has ESBLs, and avoid the
use of all cephalosporins, and all penicillins. Associated
resistance may be to aminoglycosides and
fluoroquinolones! The best test for ESBLs is perhaps to
test for synergy between ceftazidime and clavulanic
acid (Drusano, 1998).
If you're going to use beta-lactamase inhibitors
for organisms with ESBLs, you must give high
doses, or the inhibitor will be overwhelmed!

Carbapenems are perhaps best as initial

therapy if the patient has serious infection with
an ESBL-producing organism.
Klebsiella
The same points made for E. coli carrying ESBLs appy
to Klebsiella, another common pathogen that has
picked up the ESBL habit! Klebsiella species with
ESBL-gene containing plasmids are now common in
European ICUs. Plasmids rapidly spread between
different species of bacterium, for example moving
between Klebsiella , E. coliand Serratia . This spread is
made worse by transposons - "jumping genes" that
move from site to site, even jumping from plasmids to
bacterial chromosomes. (We have only recently
realised the importance of integrons, which are
discussed below).
Proteus
Proteus mirabilis may still be sensitive to ampicillin,
although in some centres resistance is present in
~50% of isolates, often due to production of
penicillinase. ESBLs in P. mirabilis have now become a
cause for concern [Int J Antimicrob Agents 2001
Feb;17(2):131-135] Such organisms may respond to
high dose piperacillin + tazobactam, or carbapenems,
amikacin. Inhibitor resistant beta-lactamases may
also be found in some clinical isolates of P. mirabilis!
Other Proteus species may respond to a 3rd
generation cephalosporin + aminoglycoside, or
perhaps piperacillin + tazobactam, or a
quinolone.
Enterobacter
Enterobacter cloacae may account for up to one
quarter of ventilator-associated pneumonias in some
studies, although one must remember that criteria for
ventilator-associated pneumonia vary from centre to
centre. Third-generation cephalosporin treatment of
Enterobacter infections (especially pneumonia) has

been associated with rapid selection of "de-repressed

mutants". These organisms produce vast amounts of
beta-lactamase all the time , because (simplistically)
they lack the "switch" that normally turns off the lactamase gene when there are no beta-lactams in the
environment. (A similar phenomenon has been seen
with Serratia and Citrobacter). 'Epidemic' spread of
the organism may then occur. Treatment of such
organisms may be limited to carbapenems, cefepime,
or possibly high-dose piperacillin+tazobactam.
(Cefepime still works in many, even if chromosomally
mediated stably derepressed 'Amp C'
cephalosporinases are present).
Pseudomonas aeruginosa
In some ICUs, this is the major pathogen causing
ventilator-associated pneumonia! Resistance to
multiple antibiotics is common, including piperacillin,
ceftazidime, quinolones; and imipenem (due to the D2
porin being dropped). Treat according to the
sensitivity profiles from your unit - one usually has to
choose between cefepime, a carbapenem, or
piperacillin+tazobactam. Combination therapy (+
aminoglycoside) is still controversial.
Stenotrophomonas maltophilia
This organism is inherently resistant to imipenem. It
usually attacks debilitated or immunosuppressed
individuals. Treatment is controversial. Co-trimoxazole
may be a treatment option, (despite it being only
bacteriostatic), or possibly ticarcillin+clavulanate. A
superb review is [Clin Microbiol Rev 1998
Jan;11(1):57-80]. The role of clinafloxacin,
sparfloxacin, and trovafloxacin is unclear, but
chloramphenicol is usually active against S. maltophilia
(if you are feeling brave)!
Burkholderia cepacia
Nosocomial outbreaks have occurred with this resilient
microbe. Patients with cystic fibrosis are particularly
prone to infection, and those who are infected appear

predisposed to death following lung

transplantation! It's worrying that the organism has
been used in agriculture as a 'biopesticide' to protect
crops from fungal infection!
Acinetobacter anitratus, baumanni and friends
Resistance to quinolones and cephalosporins is
prevalent. Other resistance is variable. It is often
difficult to decide if the Acinetobacter is merely a
coloniser, or causing harm. Treatment should be based
on sensitivity profiles of the organisms commonly
present in your unit, or the organism itself (if you've
isolated it). Quinolone resistance seems to be on the
increase.
Serratia marcescens
Where appropriate, this organism may respond to beta
lactams, aminoglycosides, or fluoroquinolones. Hejazi
and Falkiner have reviewed S. marcescens well [J Med
Microbiol 1997 Nov;46(11):903-12]. As with
Pseudomonas and Acinetobacter, quinolone resistance
is not uncommon.
Staphylococcus aureus and MRSA
Methicillin-resistant Staphylococcus aureus (MRSA) is
now a major pathogen in many ICUs, and in some
accounts for over a third of ICU pneumonias! This
pathogen is resistant to all beta lactams, as well as
quinolones, so glycopeptides are the drug of choice in
institutions where such resistance is common. Recently
we have seen the emergence of S. aureus with reduced
susceptibility to vancomycin (a great worry).
Methicillin resistant coagulase-negative
staphylococci (CNS)
Resistant to beta lactams (and a few to teicoplanin
too). CNS are commonly associated with intravascular
catheters.
Streptococcus pneumoniae (and penicillin-resistant S.
pneumoniae)

Unfortunately, S. pneumoniae resistant to penicillin are

becoming more common. Where they are not
prevalent, penicillin G is still the drug of choice;
otherwise use cefotaxime . There has been
international dissemination of several penicillinresistant clones of S. pneumoniae (from serotypes 6, 9,
14, 19 and 23). In the USA 'SENTRY' study, 1/3 of S.
pneumoniae isolates were at least partially resistant to
penicillin. Multidrug resistance is on the increase, with
significant levels of resistance to ceftriaxone,
tetracycline, and (commonly) co-trimoxazole.
Enterococci (and VRE)
Enterococcal infections are on the increase in ICU,
perhaps explained by excessive cephalosporin use, as
these bacteria are inherently resistant to
cephalosporins, including later cephalosporins such as
ceftriaxone. A lot of the patients are very sick, and one
is often not sure whether the Enterococcus is actually
causing disease, or just a coloniser! E faecalis is
commonly resistant to ampicillin, and E faecium
resistance to vancomycin is on the increase.
A few enterococci are intrinsically resistant to
vancomycin, but most of the current 'VREs',
especially E. faecium, have acquired resistance
to glycopeptides. This was probably related to
the outrageously silly, extensive use of
vancomycin in the USA in the 1980s. If your
patient has VRE infection, you have a biiig
problem. (Consider high dose
ampicillin+sulbactam if the MIC is under 64
g/ml, with an aminoglycoside if still sensitive
to this; otherwise streptogramins which may be
difficult to obtain and do NOT work against
E. faecalis ; or possibly linezolid). Cefepime is
usually still active against this organism. -->
Bacteroides fragilis
We have briefly reviewed B. fragilis elsewhere. The

organism is interesting because some isolates contain

carbapenemases!
Cl. difficile
This common ICU pathogen can cause diarrhoea or
even life-threatening pseudomembranous enterocolitis.
Prior antibiotic therapy (often with third-generation
cephalosporins, other beta lactams, or clindamycin) is
almost invariable. Treatment is metronidazole. (Avoid
oral vancomycin because of its potential for promoting
vancomycin resistance). Recurrences are common but
respond to re-treatment.
Other agents
There is marked variation between ICUs as regards
pathogenic bacteria. For example, in some instututions
(with contaminated water) Legionella has turned out to
be an important pathogen; in others Haemophilus
influenzae is a major cause of pneumonia!
Neisseria meningitidis
Patients with meningococcal septicaemia often die
rapidly despite adequate antibiotic therapy and heroic
measures. There is a superb review in Clinical
Microbiology Reviews [Clin Microbiol Rev 2000
Jan;13(1):144-66] Decreased senstivity to penicillin has
been widely reported, (due to poor PBP-2 binding), so
broad-spectrum cephalosporins such as ceftriaxone are
now recommended, started as soon as possible .
Chloramphenicol resistance has occasionally been
reported.

Sites and types of infection

"Blood borne infections"

As we said above, it's always a good idea to look diligently

for the site of origin of microbes in the blood. Karam &
Heffner have summarised the common causes of blood
borne infection, based on CDC and other data. Coagulase

negative staphylococci come out tops {how many of these

were contaminants?}, followed by Staph. aureus and
Enterococci, a surprisingly high percentage are Candidal (5
to 11%), and E. coli and Klebsiella make up some of the
remainder. If there is no other source for infection, think
about that intravenous catheter you have left in for "just
one more day"!
Pneumonia

Patients that end up in ICU with community acquired

pneumonias may be infected with a variety of organisms,
including S.
pneumoniae , Haemophilus , Klebsiella , Legionella ,
and
even Mycoplasma , Chlamydia , and so on. ICU- and
ventilator-associated pneumonias (VAP) are difficult to
diagnose and manage, and are commonly due to
multiresistant gram-negative organisms, although recently,
resistant gram positives have become prominent. VAP is by
far
the
most
important
infection
in
ICU.
Think Pseudomonas , Klebsiella ,Acinetobacter , and also S.
aureus . One possible solution to overuse of antibiotics is
short course quinolone therapy, with reassessment at 3 days
[Am J Respir Crit Care Med 2000 Aug;162(2 Pt 1):505-11].
There is scant evidence that invasive assessment of VAP
alters outcome. See for example [Am J Respir Crit Care Med
2000 Jul;162(1):119-25]. Gram stain of sputum in VAP is of
mimimal value. Causative organisms of VAP vary widely
from ICU to ICU.
Urinary tract infection

While community-acquired UTIs are often due to E. coli , in

hospital the usual nosocomial gram negatives are also often
responsible.
Intra-abdominal infections

Here too, E. coli is important, but a host of other gram

negatives may participate, enterococci often add to the
problem,
and anaerobes are
extremely
important,
especiallyBacteroides fragilis . Remember that infections
are often polymicrobial.

Surgical wound infection

Both staphylococci and gram negatives (often hospitalacquired) are important.

Meningitis

In adults the main organisms are Neisseria meningitidis,

and Streptococcus pneumoniae. Long-term neurological
sequelae are common, if the patient survives. If the person
is immune compromised, think Gram -ve bacilli, Listeria
monocytogenes , fungal infection, and mycobacteria. It is
not uncommon for doctors to mis-diagnose tuberculous
meningitis as an acute bacterial meningitis because (a) they
haven't taken a decent history and (b) the initial
leukocytosis in the CSF may confuse them. Pseudomonas
meningitis is uncommon but difficult to treat, and outcome
is often poor. Imipenem should be avoided as it may cause
seizures,
but
meropenem
is
safe,
although
an
antipseudomonal penicillin (such as ceftazidime) is perhaps
preferable, unless resistance is suspected.
Immune compromise

We will not here discuss the immune-compromised patient

in any detail. Suffice it to say that many ICU patients are
subtly or even overtly immune compromised, due to their
poor nutritional status. There are others who may be on
corticosteroids,
and
a
small
subset
on
potent
immunosuppressives, or with underlying disease (such as
AIDS) which predisposes to attack by a host of 'normal
pathogens', as well as numerous fungi (like Pneumocystis
and Candida), parasites, and opportunistic bacteria. In
neutropaenic
sepsis,
aggressive
and
above
all urgent management for presumed Gram negative
infection will be life-saving.

Topics of Interest
What is an integron ?

Integrons are very important, because they are

the main mechanism for dissemination of resistance genes

in Gram negative bacteria. Let's start by describing the

structure of an integron. An integron has:
A strong promoter site;
A gene coding for an enzyme called an integrase (the
'intl' gene);
A 'recombination site' (the fancy abbreviation for this
is attI ).
The basic idea is that the integrase catalyzes insertion or
deletion of resistance genes, and these are then vigorously
expressed due to the strong promoter site. Resistance
genes can spread aggressively between bacteria. These
genes that can be clipped out of one integron and inserted
into another are called gene cassettes (Something like
taking a tape recorder cassette and playing it on somebody
else's tape deck)! The cassettes are inserted at the attI site,
which is recognised by the integrase. Up to five (or possibly
even more) resistance genes may be contained in a single
integron. There are over 60 gene cassettes described,
including those that code for ESBLs and carbapenemases.
Other cassettes code for resistance to aminoglycosides,
trimethoprim, chloramphenicol, and even antiseptic agents
such as quaternary ammonium compounds and mercury!
Different intl genes have been described. There are at least
six, with classes 1, 2 and 3 being considered most important
in spread of antibiotic resistance. Integrons have been
around for a long time - we just haven't been really aware of
them until recently. (See the review in [Clin Chem Lab Med
2000 Jun;38(6):483-7] ).
Most integrons have been reported from gram negatives
(especially Enterobacteriaceae). "Super-integrons" have
also been described, harbouring hundreds of genes, for
example in Vibrio species.
Thoughts about predisposition to development of resistance

It makes sense that the larger the population of bacteria,

and the longer they are exposed, the more likely they are to
develop
resistance
to
a
particular
antimicrobial.
Remembering that the largest natural reservoir of bacteria
in man is the bowel, it then comes as no surprise that
agents that are extensively excreted into the bowel should
promote ready resistance, especially if they persist for long
periods
of
time
(eg.
rifampicin).
Likewise,
oral
administration of vancomycin, a silly idea which should be
avoided if at all possible, will probably promote vancomycin
resistance, while intravenous administration should be far
less likely to do so, as the drug is then renally excreted.
Mechanisms of Resistance

We have discussed this elsewhere.

Do ICUs export resistant bugs?

There is some evidence suggesting this is the case. See for

example [ Clin Infect Dis 1999 29 1411-18 Lucet et al ].
ICUs are often jam-packed with resistant micro-organisms,
accounting for up to a quarter of all nosocomial infections
(despite constituting under 5% of beds in most hospitals).
Does initial appropriate therapy lower mortality?

Yes. See [ Chest 1999 115 462-74, Kollef et al].

Does good empiric therapy prevent drug resistance?

Yes. See [ Ann Intern Med 1996 124 884-90, Pestotnik et

al].
Bactericidal vs bacteriostatic antibiotics?

It is often recommended (without support from a vast

amount of research) that bactericidal antibiotics are
preferable to bacteriostatic ones, with severe ICU
infections. Examples of bactericidal antibiotics are
penicillins, cephalosporins, aminoglycosides, carbapenems,
and fluoroquinolones.
Endotoxin release by antibiotics

We know that gram negative bacteria release endotoxin

from their cell walls when proliferating and when dying,

and it is this endotoxin that initiates many cellular events

(such as cytokine production) that cause morbidity and
mortality. An attractive hypothesis (with little current
substantiation or refutation) links administration of some
antibiotics, massive bacterial killing, endotoxin release, and
patient deterioration. We are not convinced that such
endotoxin release is clinically significant.
If I stop using an agent, will resistance to it disappear?

No. Resistance will be suppressed, but the chances are that

the resistant organism will still lurk in the background, and
reappear quickly in large numbers, once it is encouraged to
appear by suppression of the competition (when you start
using the agent enthusiastically once more).
Dosing considerations - infusions and stat doses

Aminoglycosides kill bacteria based on high concentrations,

and because (unlike most other agents) they have a postantibiotic effect (PAE) that may last several hours, should
probably be given in high doses once a day, rather than
smaller doses twice or more per day. Although quinolones
don't have a PAE, they too kill depending on concentration,
and so area under the plasma concentration-time curve is
important in determining bacterial kill rates.
On the contrary, beta-lactam killing of bacteria depends on
the amount of time the tissue levels are above the minimum
inhibitory concentration (MIC), and (above this level) is
concentration-independent. It is therefore logical to give
penicillins by continuous infusion, and it is unclear to me
why so many people are still giving their penicillins as
intermittent push-ins! (Probably just a matter of
convenience and tradition flying in the face of reason). See
for example Craig & Ebert [Antimicrob Agents Chemother
1992 36 2577-83], and Drusano (1998).
Where can I get consensus guidelines on preventing spread of resistant microorganisms?

Try:
Goldmann et al [JAMA 1996 275 234-40]

 Shlaes et al [Clin Infect Dis 1997 25 584-99]

Weber et al also have a lot of detail, especially on
management of MRSA outbreaks.
Crop Rotation

Kollef et al from St Louis [Crit Care Med 2000 28.10 345664], in the context of increasing incidence of microbial
resistance, pursued the idea of scheduled changes in the
class of antibiotics used for empirical therapy. (Some have
called this "crop rotation", or "heterogeneous antibiotic
use"). They rotated (for periods of six months) from a
baseline of ceftazidime, through ciprofloxacin, and then
cefepime, showing a progressive decline in the primary
outcome - incidence of inadequate antimicrobial treatment.
This incidence was assessed by isolation of the causative
organism, and sensitivity testing where appropriate.
Approximately 3/4 of the 3668 patients received antibiotics,
including about a quarter who received "post-operative
prophylactic antibiotics". 37% of patients had an identified
infection, 90% of these being ventilator-associated or
"bloodstream" infections. Inadequate antimicrobial therapy
(use of a 3rd generation cephalosporin against a resistant
organism, and to a lesser extent MRSA, Candida, VRE) was
associated with increased in-hospital mortality. The study
could perhaps be faulted because there was no
simultaneous division of the study population into two
groups - one group receiving therapy based on "the current
crop", and the other at the discretion of the attending
physician. The limitations of the study are well-discussed in
the article.
Also note the potential concerns about crop rotation,
notably cross-resistance. See [ J Antimicrob Chemother
1992 29 307-12] and [Antimicrob Agent Chemother 1990 34
2142-7] for cross resistance between quinolones and
imipenem!