Cases & Commentaries

Inappropriate Antibiotic Use

Commentary By Hilary M. Babcock, MD; Victoria J. Fraser, MD

The Case

A 41-year-old woman presented to the hospital
with acute renal failure, which came to be diagnosed as a first
presentation of systemic lupus erythematosus (SLE). During the
hospitalization, she developed additional complications of SLE
including cerebritis, hemolytic anemia, and thrombocytopenia.

After 2 weeks in the hospital, the patient was
given vancomycin and piperacillin/tazobactam for altered mental
status and leukocytosis of 19,000. A few days later, antibiotics
were changed to vancomycin and levofloxacin for persistent
leukocytosis and low-grade fevers. Multiple cultures from urine,
blood, and sputum yielded no organisms, but the patient was kept on
antibiotics due to fevers. Although no clear source of infection
was identified, antibiotics were continued for 3 weeks, at which
point her fevers spiked to 38.5°C. At that time, a single blood
culture grew vancomycin-resistant Enterococcus faecium
(VRE), as did a central line catheter tip. Furthermore, urine
cultures grew more than 100,000 colonies of Candida
glabrata
.

The patient received a consultation from an
infectious disease (ID) specialist, who recommended that all
antibiotics be discontinued. Within 24 hours, the patient
defervesced. She remained hemodynamically stable and underwent
further treatment for her SLE.

Additional information: Although the ID
consultants would have preferred to treat the VRE with linezolid,
the patient’s severe thrombocytopenia and anemia prohibited
its use. Thus, she was given doxycycline, a second-line agent for
this organism, and had her central venous catheter discontinued. A
repeat blood culture grew VRE, which necessitated removal and
re-placement of yet another central venous catheter. In an attempt
to clear colonization of
C glabrata, multiple Foley
catheters were changed, and the organism eventually was eliminated.
Initiating immunosuppressive treatment for the patient’s SLE
had to await eradication of the resistant organisms.

The Commentary

Nosocomial infections and antibiotic-resistant
organisms are two common problems among hospitalized patients. This
case clearly illustrates how the confluence of these two
problems—nosocomial infections caused by antibiotic-resistant
organisms—makes management challenging.

Of the more than 2 million nosocomial infections
each year in the United States, 50%-60% are caused by
antibiotic-resistant organisms.(1)
This high rate of resistance has been identified as an urgent
national problem; it increases the morbidity, mortality, and costs
associated with nosocomial infections. Among gram-positive
bacteria, the most important resistant pathogens are
vancomycin-resistant Enterococcus, beta-lactam resistant and
multi-drug resistant streptococci, and methicillin-resistant
Staphylococcus aureus. From 1990 to 1997, the prevalence of
vancomycin-resistant Enterococcus increased from 1)

Multiple factors may contribute to increasing
antibiotic resistance, including increased severity of illness;
more severe immunosuppression; newer invasive devices and
procedures; increasing levels of antibiotic resistance in the
community; suboptimal use of isolation and barrier precautions
leading to cross-transmission and outbreaks; increased use of
prophylactic and empiric antibiotics; and higher overall antibiotic
use per area, per unit time.(2)
Prolonged length of hospital stay also seems to predispose patients
to infection with antibiotic-resistant bacteria, possibly due to
the greater likelihood over time of becoming colonized with
resistant bacteria, either from horizontal nosocomial transmission
or endogenous emergence of resistance.(3)

In this case, antibiotic initiation was prompted
by low-grade fever and leukocytosis, both common reasons for
antimicrobial treatment. However, fever should not be seen as an
automatic indication for antibiotics. Fever can have many causes in
hospitalized patients, including non-infectious etiologies such as
drug fever, thromboemboli, atelectasis, or an underlying illness.
Some infectious causes, like viral and fungal infections, will not
benefit from treatment with antibiotics. In febrile patients,
evidence of a bacterial infection should be sought diligently with
blood and urine cultures, urinalysis, a chest x-ray, and a careful
physical exam with special attention to the skin for soft tissue
infections, infections associated with venous catheters, or
evidence of cutaneous emboli. Continued fever following the
initiation of antibiotics may indicate a non-infectious etiology,
or an infectious cause not covered by antibiotics.

In this patient, fever, leukocytosis, and mental
status changes could all be attributed to her SLE. However, the
distinction between fever from infection and fever from other
sources can be difficult to make prospectively. This patient is
also at increased risk for infection due to her underlying disease
and its likely treatment with corticosteroids. Starting antibiotics
in these circumstances is not necessarily an error, but continuing them
for 3 weeks without clear evidence of a bacterial infection is.

In severely ill patients, the desire to start
antibiotic treatment early and with broad-spectrum agents is
understandable, especially given recent data showing an association
between inadequate initial antimicrobial therapy and increased
mortality among intensive care unit patients.(4,5) However, not all patients require immediate
antibiotic treatment. Broad-spectrum empiric coverage benefits
patients in intensive care units who are critically ill with
hemodynamic instability or severely immunocompromised patients.
Patients who are clinically stable without any clear focus of
infection usually are not harmed by waiting until culture results
are available before starting antibiotics. When the choice is made
to begin empiric antibiotic coverage, if no evidence of bacterial
infection is found, all antibiotics should be stopped, even in the
face of persistent fevers. In hemodynamically unstable patients or
patients with significant immunosuppression, if clinical suspicion
for a bacterial infection is high, antibiotics may be continued
even if cultures are negative. In these cases, a reasonable course
of therapy (7-10 days) should be administered and then antibiotics
should be stopped. This is also true if a patient was pre-treated
with antibiotics, which may render the culture results unreliable.
After antibiotics are stopped, the patient can be monitored
clinically and recultured to evaluate any new symptoms or signs of
infection. If a bacterial infection is identified, the culture and
susceptibility data should be used to narrow the antibiotic
coverage as soon as possible.(6)
Physicians should evaluate the patient’s response to
treatment daily and re-evaluate the continued need for
antibiotics.

In this case, although initial empiric
broad-spectrum antibiotic coverage was considered necessary,
stopping therapy on the basis of negative cultures was imperative.
Why? Because prolonged exposure to broad-spectrum antibiotics
increases the risk of colonization with resistant organisms and
subsequent infection with resistant bacteria--not just at a
population level but also in an individual patient. Prolonged
exposure to broad-spectrum antibiotics predictably increases the
risk of overgrowth of Clostridium difficile and of
subsequent colitis, the risk of overgrowth of vancomycin-resistant
Enterococcus and methicillin-resistant Staphylococcus
aureus
, and the risk of fungal infections. Many physicians find
it hard to limit antibiotic use when they think that broad-spectrum
antibiotic coverage is in the patient’s best interest,
despite possible societal consequences such as increasing
antibiotic resistance in the hospital. This case illustrates very
well how societal needs and the needs of individual patients are
not in conflict: they are generally the same.

Colonization is often a precursor to infection.
This patient’s urine cultures with C glabrata were
recognized as colonization and managed appropriately, by changing
the catheter (removing it if possible) and minimizing the use of
broad-spectrum antibiotics. A urinary tract infection (not just
colonization) might be signaled by persistently positive cultures,
consistent symptoms such as dysuria, pyuria, or evidence of upper
tract disease. In those cases, antifungal therapy would be
indicated. Colonization of central lines can likewise herald
infection. When blood cultures drawn from a catheter are positive
(even in the absence of positive peripheral blood cultures), the
line and/or the catheter hub can be considered colonized and the
line should be removed.

How can overuse of antibiotics be prevented?
Strategies to improve antibiotic stewardship and reduce antibiotic
resistance have recently been summarized.(3) Educational programs for all physicians, including
personal interactions, detailed information on local susceptibility
patterns, and feedback on prescribing practices, can change
behavior.(7)
Hospitals can also develop guidelines for antibiotic use. In some
settings, these guidelines are maintained on a Web site for easy access by
working physicians. These guidelines can be supplemented with
informatics support including prescribing reminders, formulary
restrictions, and automatic stop alerts. Involvement of infectious
disease specialists increases the likelihood that patients receive
adequate empiric antibiotic therapy and is also associated with
less use of unnecessary broad-spectrum antibiotics, more rapid
shift to oral agents, and reductions in infections with resistant
organisms.(3)
Perhaps most effective of all, some hospitals have developed robust
computerized decision support to help guide physicians to better
choices about antibiotic usage. These programs, which can
constantly integrate updated information on pathogen prevalence and
local resistance patterns, have led to marked improvements in the
appropriateness of antibiotic use, the costs of care, and the
frequency of antibiotic resistance.(8,9)

Effective infection control programs are also
crucial.(10,11)
Studies have shown that rates of catheter-related bloodstream
infection can be decreased with proper catheter insertion technique
and care. Educational interventions addressing these issues should
target practicing physicians and trainees.(12,13) Additionally, infection control programs are
instrumental in setting, enforcing, and educating staff about the
importance of isolation and barrier precautions as well as hand
hygiene for the prevention of cross-transmission of resistant
organisms.

Take-Home Points

  • Consider non-infectious causes of
    fever.
  • Obtain appropriate cultures and use susceptibility
    results to guide antibiotic therapy.
  • Antibiotics should be
    stopped when there is no evidence of bacterial infection. If
    antibiotics are continued in immunocompromised or unstable patients
    with negative cultures, a defined course of therapy (7-10 days)
    should be administered and then
    discontinued.
  • Broad-spectrum empiric antibiotics should be
    changed to narrow-spectrum agents when susceptibility results are
    available.
  • Antibiotic use should
    be evaluated frequently in each patient to determine the response
    to therapy and its duration.(14)
  • Well-supported infection control programs can
    offer important mechanisms (contact isolation, surveillance, and
    guidelines) for preventing the spread of antibiotic-resistant
    organisms.(15-19)
    The integration of infection control and informatics yields
    considerable promise for improving the quality of care in this
    area.
  • Use of invasive
    devices, and the duration of their use, should be minimized.
    Adherence to standards for insertion and care can decrease the risk
    of infection.(12)

Hilary M. Babcock,
MD
Instructor of Medicine
Infectious Disease Division
Washington University School of
Medicine

Victoria J. Fraser,
MD
Professor of Medicine
Infectious Disease Division
Washington University School of Medicine

References

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