Affiliations: Bridgeport, CT
Dr. Manthous is Assistant Clinical Professor of Medicine, and Dr. Yaw Amoateng-Adjepong is Instructor of Medicine, Division of Pulmonary and Critical Care, Bridgeport Hospital and Yale University School of Medicine.
Correspondence to: Constantine A. Manthous, MD, FCCP, Bridgeport Hospital, 267 Grant St, PO Box 5000, Bridgeport, CT 06610; e-mail: email@example.com
Over the past decade, clinicians have
witnessed an unprecedented increase in the emergence and spread of
antibiotic-resistant bacteria.1–3 These include
methicillin-resistant Staphylococcus aureus (MRSA),
vancomycin-resistant enterococcus (VRE), multiple drug-resistant
Gram-negative rods, and resistant Streptococcus
pneumoniae. ICUs are the leading incubators of many of these
In this issue of CHEST (see page 146), Kollef and colleagues
demonstrate that ineffective therapy of resistant microorganisms is
associated with increased mortality in critically ill patients.
Clinicians at Barnes-Jewish Hospital used effective
antibiotics empirically for the vast majority of patients with
Gram-negative rod bacteremias. However, for patients with certain
pathogens (MRSA, VRE, and Candida), the initial antibiotics used were
not effective. Delays in instituting effective agents resulted in a
higher mortality rate among these patients. Independent risk factors
for development of resistant infections included previous treatment
with antibiotics, presence of a central venous catheter (for longer
duration), and low serum albumin levels. These factors are likely to
help identify “at-risk” patients at most institutions. Should we
assume infections with antibiotic-resistant pathogens in every patient
with one of these risk factors? If not, at what prevalence of
antibiotic resistance should we include coverage of resistant organisms
in empiric treatments? If we liberalize our use of the ever-decreasing
list of effective antibiotics, aren’t we promoting emergence of more
multiresistant organisms, including the dreaded vancomycin-resistant
The emergence of antibiotic-resistant organisms is not
new.7 Microorganisms have always been endowed with genetic
mechanisms for attaining resistance.5–6 Clearly, our
overuse of broad-spectrum antibiotics has accelerated the process of
microbial resistance.1,8–9 Resistance rates are highest in
the ICUs of most institutions1–5,10 due largely to
overuse of antibiotics and cross-transmission. We can no longer assume
that this is arcane “test-tube science” that can be ignored,
counting on the pharmaceutical industry to stay one step ahead of
resistant microbes through development of new antibiotics. We must lead
in scrutinizing our (personal and aggregate) antibiotic prescribing
patterns and in developing comprehensive institutional programs to
minimize the emergence and further spread of these microbes. To the
extent that patients move in and out of the ICU to various units of the
hospital, our efforts will fail if control measures are limited only to
the ICU. Solutions will necessarily require collaboration with other
hospital personnel and integration of efforts, ie, a
consistent, systematic, united front.
What should be our “first-line agents” in this era of resistant
pathogens? Since the prevalence of resistant bacteria varies between
and within institutions, the appropriate antibiotic choices for empiric
therapy will necessarily vary between hospitals and will change with
time. Interestingly, the problem of resistance had already impacted
clinicians at Barnes-Jewish Hospital insofar as vancomycin was used“
commonly” in their empiric cocktails of antibiotics. At many
centers, where MRSA is not so prevalent, vancomycin is not used
routinely. A prevalence of 15 to 20% resistance is, perhaps, a
reasonable threshold to begin routine empiric coverage for resistant
organisms in critically ill patients. The following general concepts
are relevant to the discussion:
1. Initial Approach to Individual Patients: Clinicians should
consider the balance between host (immunocompetence) and microbe
(virulence) in determining the risks and benefits of immediate vs
deferred and broad- vs narrow-spectrum treatment. The available
clinical data (ie, the likely site of infection and
organisms to which the host is susceptible) and the microbial
resistance patterns at the institution should be considered in
selecting antibiotics of adequate, but not unnecessarily broad,
spectrum to cover the probable causes of infection.
2. Use Microbiology Antibiotic Susceptibility Results To Narrow the
Attack: We must obtain culture/sensitivity results promptly, and
modify the antibiotic(s) with the narrowest spectrum and/or lowest
resistance potential11 to which the isolated organism is
3. Use Optimum Doses for a Full Course of Treatment: The
optimum doses12–13 of antibiotics should be continued for
the full course to reduce the likelihood of selecting a resistant
pathogen that will cause recurrent clinical disease. Unfortunately, for
some sites of infection insufficient data exist to inform the optimal
duration of therapy. Moreover, optimal duration could vary depending on
the causative microbe, the severity of infection, and the
immunocompetence of the host.
4. Avoid Antibiotic “Surfing”: Clinicians should allow a
reasonable time (which may vary for differing hosts/infections) for
clinical improvement before declaring an antibiotic failure. In some
severe infections, fevers may persist for up to a week. If the microbe
is sensitive (in the laboratory) and the patient is otherwise
improving, persistent fever should not, in itself, be considered
5. Hospital Infection Control: Resistant microbes will
continue to emerge, but we can attenuate the rate of spread by
implementing effective control measures. We must continually remind all
staff who care for, or come in direct contact with, patients to adhere
to standard precautions because we (health-care workers) are vectors
for nosocomial infections. The available data suggest that we are
abysmal in both the frequency and quality with which we wash our hands
between patient contacts.14 Multiple drug-resistant
nosocomial infections are unlikely to be reigned in unless this simple,
yet difficult, step is taken. Physician-leaders should lead by example.
The risk of transmission is greatest while awaiting culture
results. Extra precautions should be initiated when the admission data
suggest the possibility of resistant, highly transmissible pathogens
like VRE or MRSA. Waiting until cultures return unnecessarily increases
risk of transmission to other patients. One approach is to place all
patients with risk factors (history of MRSA or VRE infection, transfer
from nursing homes, Gram’s stain data indicating Gram-positive cocci
in clusters, and/or long-term IV catheters) in contact isolation until
infection/colonization has been ruled out. For example, in our critical
care unit, patients are placed in precautionary contact isolation if
any Gram’s stain of a body fluid reveals Gram-positive cocci in
clusters, or cultures reveal staphylococcal infection and we are
awaiting antibiotic sensitivities. But, this common-sense, preventative
measure has not been proven to reduce the frequency of such infections
and may not be cost-effective.
6. Institutional Restrictions on Antibiotic Use: Selective
restriction, removal, or control of antimicrobial agents, particularly
those with high resistance potential, may be important means of
reducing the emergence of multiple drug resistance. Implementation of
such measures in some institutions has resulted in reductions in the
prevalence of resistant organisms.15–16 Arbitrary rotation
of classes or agents used in empiric cocktails may inadvertently
increase the prevalence of multiple drug resistance. Such strategies
are only likely to be helpful if they utilize microbial surveillance
data to switch classes/agents when resistance emerges. Moreover, the
use of centralized formulary restrictions and rotating crops of agents
can only be successful if all stake-holders—intensivists, infectious
disease specialists, hospital epidemiologists, pharmacists, and policy
makers—coordinate their efforts (and staff physicians are convinced of
the importance of such initiatives).
The emergence of multiple drug-resistant pathogens poses a new
challenge to all. As intensivists, our critically ill patients will pay
the heaviest price. Thus, we must lead the way in modifying
clinicians’ behaviors (ie, appropriate antibiotic selection
and dosing, and hand washing) and formulate comprehensive strategies to
contain resistant infections, thus reducing the risk to present and
future patients. Increasing scientific attention to this problem will
yield proven solutions that can be instituted in the future. In the
meantime, let’s make hand washing between patient contacts, one proven
method of infection control, the 11th commandment in the ICU (and
throughout the hospital).
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