CASE 18

A 74-year-old woman has been in the ICU for 8 days for the management of re
current urinary tract and blood-borne infections. She has a history of a cerebral
vascular accident and residual neurological deficits and has been hospitalized for
the past 3 weeks. A nurse notifies you for temperature of 39,4 C. On
examinatiion, her pulse rate is 100 beats/minute, respiratory rate is 22 breaths/
minute, and blood pressure is 110/84 mm Hg. The patient is currently on the third
day of ciprofloxacin for empiric treatment of her recurrent urinary tract infection.
Her serum creatinine is 2.2 mg/dL Her urine culture reveals multidrug-resistant
(MDR) Acinetobacter baumannii and the blood culture reveals the same organism
in addition to fungus.

What is the most appropriate next step in the management of this patient?
What are the underlying processes that predispose to this oondition?
What are appropriate strategies in the prevention of this problem?

A N SW E RS T O CAS E 1 8 :
Antim icrobial Use in I CU

Summary : An elderly 74-year-old woman with a prolonged hospitalization now

has a urinary tract infection and bacteremia with multidrug-resistant (MDR)
bacteria. She has an elevated temperature despite antibiotic treatment and has
developed fungemia as well.

Next step: Administer appropriate therapy to cover the MDR bacterial infection
and fungal infection.
Underlying predisposing processes: The factors in this patient contributing to
MDR bacterial and fungal infection are prolonged hospitalization, comorbid
conditions, recurrent or persistent infections, relatively immunocompromised
state, and previous antibiotic exposures.
 Prevention of resistance: Provide prompt broad-spectrum antibiotics for empiric
therapy followed by antibiotic de-escalation after culture sensitivities become
available and when patient shows good clinical responses to the initial therapy.

ANALYSIS
Objectives
1 . To learn the principles of antimicrobial selection and treatment endpoints in
ICU patients.
2. To learn antimicrobial treatment strategies that may reduce the occurrence of
antimicrobial resistance.
3 . To learn the supportive care that may improve responsiveness to antimicrobial
treatment in the ICU population.

Considerations
This is a 74-year-old woman with significant residual neurologic deficits and
renal insufficiency after suffering from a cerebral vascular accident. She has had a
prolonged hospital course and is now in the ICU after contracting a nosocomial
infection.
She is currently on antibiotics but does not appear to be improving. When a
patient does not respond to antimicrobial therapy, it is generally important to
determine if another source of infection is present and/or if the antibiotic
treatment regimen is inappropriate or insufficient against the microorganisms
responsible for the infection. The culture results at this point are helpful in
directing her management.
Since the same bacteria is isolated from her urine and her blood stream, the
infection is severe, systemic, and inadequately controlled with the current
antimicrobial regimen. In addition, fungal species isolated on blood culture
strongly suggests that fungal sepsis is contributing to the worsening clinical
picture. Infection with drug-resistant organisms contributes to prolonged
hospitalization, higher hospital costs, and a poorer prognosis. Unfortunately, this
patient represents a common clinical scenario in many modern ICUs.
The most important first steps in this patient's management is selection of the
correct antimicrobial agents and dosages based on the sensitivity spectrum of the
cultured MDR A . baumannii and fungal species. Assistance from the institution's
microbiology laboratory and infectious disease specialists should be sought out to
coordinate the management of her complicated infections. The emergence of
antibiotic- resistant bacteria is a significant problem in intensive care units. This
resistance makes antimicrobial therapy more difficult as patient's disease process
and illness severity continue to increase. The inappropriate administration of
broad-spectrum antibiotics can lead to even more difficult-to-treat infections.

D E FINITIONS
NOSOCOMIAL INFECTIONS : Infections acquired in a health-care facility.
Generally, the infectious organism is first cultured >48 hours after admission.
HEALTHCARE-ASSOCIATED INFECTIONS : Infections in patients with prior
hospitalization for > 3 days within the past 90 days, transferred from nursing
home, or history of exposure to transfusion/dialysis centers.
EMPIRIC ANTIBIOTIC THERAPY: Antibiotic therapy that is started without
culture evidence of infection. The therapy is started based on clinical suspicion of
infection based on physiologic parameters.
ANTIMICROBIAL DEESCALATION: The goals of the de-escalating strategy
are to strike a balance between providing prompt, appropriate initial antimicrobial
therapy and minimizing the emergence of antimicrobial resistance. Patients with
suspected infections are treated with broad-spectrum antibiotics aimed at most
probable organisms that are causing the infections with narrowing (or
discontinuing altogether) of the antibiotic coverage as soon as culture results
become available, or if no infections are documented. Similarly, duration of
treatment may be shortened when patients with uncomplicated infections show
clinical improvement/resolution.
ANTIBIOTIC RESISTANCE: The ability of microorganisms to grow in the
presence of antibiotic levels that would normally suppress growth or kill
susceptible bacteria.
CLINICAL APPROACH
Nosocomial infections affect ICU patients with far greater frequency than patients
residing elsewhere in the hospital. Consequently, antibiotics are one of the most
common therapies utilized in the intensive care unit. Additionally, up to 70% of
all nosocomial infections isolated in the ICU are due to MDR bacteria. The reason
for this elevated level of drug-resistant infections is multifactorial. ICU patients
have a more severe underlying disease processes, are crowded into small areas of
the hospital, and are often malnourished and immunocompromised.

They are more likely to be subjected to multiple invasive procedures including

endotracheal tubes, indwelling urinary catheters, and central venous lines. In
addition to patient-specific risk factors, there are other general factors such as
excessive antimicrobial use, poor aseptic technique, and inadequate hand hygiene
of health-care providers that contribute to the increased infectious risks. The
inappropriate choice and duration of antibiotics therapy can also contribute to the
problem by selecting for resistant bacteriaovergrowth and infection. Microbial
resistance is increasing in both gram-negative and gram-positive bacteria. These
bacteria strains have greater resistance to broad spectrum antibiotics. The
inadequate empiric coverage of these resistant bacteria can lead to a higher
morbidity and mortality. However, the inappropriate use of broad-spectrum
antibiotics can lead to the increase in emergence of resistant bacteria. Thus, the
challenge to the physician is to use antibiotics that will cover the resistant bacteria
without overtreatment that can lead to resistance.
When a patient is septic, antibiotics must be initiated promptly, preferably, within
1 hour of diagnosis. Each hour of delay over the next 6 hours has been shown to
contribute to a decrease in survival of 7 .6%. For most septic patients, the culture
results are not known at the time of the initial presentation; therefore, antibiotics
are selected based on clinician's suspicions of the source of infection. The initial
choices of the preemptive antimicrobial therapy need to adequately address the
potential infective organisms to minimize the mortality associated with the
infection. Inadequate initial therapy usually involves either the failure to cover a
specific microbe or utilizing antibiotics to which the organism is resistant.
Therefore, high-risk patients admitted to the ICU with serious infections should be
treated aggressively with broad-spectrum antibiotics until the bacteria cultures are
isolated. It is obligatory that before antibiotics are started, cultures should be
obtained. Once the culture isolates with their associated antibiotic sensitivities are
identified, the antimicrobial therapy should be immediately adjusted to more
narrow-coverage antibiotics that have bactericidal activity against the bacteria.
This de-escalation therapy allows for treatment of the infection while reducing the
risk of antimicrobial resistance. Another key component in the selection of
antibiotic choice is based on the basic pharmacokinetics (necessary dosage to
achieve adequate levels, tissue penetrance,
etc ) .
This is important so that under-dosing does not occur, as this can lead
to an increase in the emergence of resistant organisms. This is particularly
important in patients with renal insufficiency; adjustments of drug dosing and
frequency of administrations are often needed when patient are receiving
hemodialysis. Recognizing when patients are at high risk for developing MDR
infections is important in selecting appropriate initial broad-spectrum antibiotics,
and these high-risk patients include those who have had prior antibiotics
treatments during their hospitalization, prolonged hospitalization, and indwelling
devices (such as endotracheal tubes, central venous catheters, and urinary
catheters) . Infected highrisk patients should be started on combination broad-
spectrum antibiotics based on presumed infectious sources and local antibiograms
(Table 1 8-1 ) .
Initial antibiotics are selected based on knowledge of the infection source.
Antibiotics have different tissue penetrations and should be taken into account
when treating infections. Source control of the infection, such as abscess drainage,
should be performed immediately.
The choice of antibiotics is somewhat dependent on the local hospital flora.
Different resistance rates are found at different hospitals, so antibiograms that
show local antibiotic susceptibility should be used as a guide for initiating therapy
that will cover local resistance. Once the cultures return with antibiotic
susceptibility, antibiotic therapy should be de-escalated in spectrum and duration.

If no organism is isolated after 72 hours, serious consideration should be given to

stopping the antibiotic administration. In a study evaluating the duration of
therapy in treating patients with ventilator-associated pneumonia (YAP) , it was
determined that treating patients for 8 days instead of the standard 1 5 days had no
differencein mortality, but significantly reduced the incidence of MDR bacterial
infection.
Patients with spontaneous bacterial peritonitis receive no additional benefits from
being treated for more than 5 days with cefotaxime ( Claforan) . For all other
isolated organisms, the antibiotics should be stopped after a predetermined time
course. This allows for shorter therapy with decreased likelihood of selecting
resistant organisms.
It is also more economical to not provide prolonged, unnecessary antibiotic
therapy. However, these maneuvers must all be undertaken after taking into
consideration with the patient's clinical status. If the patient continues to remain
septic, or is clinically deteriorating, antibiotic administration can be prolonged.
Likewise, patients who are immunocompromised or elderly may benefit from
longer durations of antibiotics therapy.
There are other strategies that are used in the ICU to decrease infection rates.
Specific strategies that have been shown to decrease the rate of central-
lineassociated bloodstream infections ( CLABSI) when used in combination
include hand hygiene, the use of full sterile barriers during central-line insertion,
skin antisepsis with 2 % chlorhexidine solution, subclavian vein insertion site,
chorhexidine- impregnated sponge dressings at the line sites, centralizing
equipment in a central-line carts during catheter insertion, and daily assessment of
centralline necessity. Strategies that may reduce ventilator-associated pneumonias
include the elevation of the head of bed, protocols for sedation medications, and
ventilation, which are associated with reduced ventilation days.
The early administration of enteral nutritional support also seems to decrease
infection rates, allowing for less use of antibiotics. Studies comparing enteral
feeding versus parental feeding indicate that there is a decrease in overall
infections.
Additionally, the use of enteral feeding allows for maintenance of nonspecific
mechanisms of immune protection by maintaining gut epithelium. Normal gut
epithelium provides for absorption of nutrients, exclusion of pathogenic
organisms, production of mucus, and maintenance of normal gap junctions. These
mechanisms all protect against potentially harmful bacteria. Not only does enteral
feeding aid in nonspecific immune protection, but it also helps provide continued
function of gut-associated lymphoid tissue (GALT) which is home to lymphocytes
that can produce cytokines and immunoglobulins. All of these factors help
provide improved immune function, thus decreasing the need for antibiotics.

CLINICAL CASE CORRELATION l

See also Case 1 7 (Meningitis/Encephalitis ) , Case 1 9 ( Sepsis ) , and Case 20
(Immune-Compromised Patient With Sepsis) .

COMPREHENSION QUESTIONS
1 8. 1 An 82-year-old woman is admitted to the ICU for presumed urosepsis. Her
initial blood pressure is 80/5 0 mm Hg, heart rate is 1 1 0 beats/minute, and
oxygen saturation is 1 00% on 2 L nasal cannula. Urine, blood, and sputum
cultureswere drawn in the emergency department. Her hemodynamics improve to
120/80 mm Hg and heart rate of 80 bpm after administration of 2 L of normal
saline and remain stable. She is started on IV vancomycin. Three days later, all
of her cultures return with no growth to date. The next step in management
should be:
A. Continue IV vancomycin for 8 more days
B. Continue IV vancomycin for 3 more days
C. Switch to ciprofloxacin PO for 3 days
D. Discontinue antibiotics completely
E. Re-culture the patient

1 8. 2 A 34-year-old man is seen in the emergency department with fever, chills,

nausea, and vomiting 2 days after injecting heroin intravenously. Which of the
following is the correct order of antibiotic management?
A. Obtain cultures, start specific monotherapy antibiotic, change to broadspectrum
antibiotics if resistant bacteria are found.
B. Start broad-spectrum antibiotics, pan culture (blood, urine, sputum) , narrow
coverage after 72 hours.
C. Start broad-spectrum antibiotics, culture in 3 days if no improvement,
de-escalate antibiotics based on culture results.
D. Obtain blood cultures and obtain a CT scan of the abdomen. If the CT is
normal, observe the patient until cultures become available.
E. Pan culture, start broad-spectrum antibiotics, de-escalate after culture
results return.

1 8.3 Which of the following measures decreases the risk of developing antibiotic
resistance in the ICU ?
A. Central-line skin preparation using povidone-iodine ( Betadine )
B. Antibiotic de-escalation
C. Restricting broad-spectrum antibiotics usage
D. Continued antibiotic administration for 2 weeks
E. Using peripherally inserted central venous catheters ( PICC) rather than
standard central venous catheters
1 8.4 A 3 2-year-old woman with a history of poorly controlled Type 1 diabetes
had a below knee amputation 2 months ago for gangrene of her foot. Her
postoperative course was complicated by a UTI and pneumonia. Her amputation
wound spontaneously opened 2 days ago and she was pan-cultured. Her wound
was satisfactorily debrided in the operating room and she was started on IV
vancomycin and IV piperacillin and tazobactam (Zosyn) . She is now being
transferred to the ICU for worsening hyperglycemia and dehydration. Her wound
culture has grown methicillin-resistant S taphylococcus aureus (MRSA) that is
sensitive to vancomycin. All other cultures were negative. What is the next step in
management?
A. Glucose control and narrow her current coverage to vancomycin.
B. Glucose control; continue her current antibiotics and add cefepime.
C. Glucose control and continue her current regimen.
D. Stop her current antibiotics and perform above knee amputation for
source control.
E. Continue current antibiotics and obtain additional cultures.
1 8.5 An 89-year-old woman who is significantly malnourished is in the ICU with
Pseudomonas aeuriginosa pneumonia. She has received 5 days of antibiotics, but
still has copious amounts of sputum and is continuing to require a significant
amount of ventilatory support. The most appropriate course of action is:
A. Continue her current regimen, but re-culture for any spikes in temperature.
B. Discontinue her antibiotics on day 8 of therapy.
C. Broaden her antibiotics for the next 24 hours and then stop antibiotics.
D. Stop antibiotics, re-culture, and await culture results before re-starting
antibiotic therapy.
E. Empirically add an antifungal agent.

ANSW ERS TO QUESTONS

1 8. 1 D. This patient presented to the emergency department hypotensive and
tachycardic and although it was initially thought that she might be septic, none of
her cultures returned with any bacteria. Additionally, she improved with simple
rehydration, indicating that she was possibly just dehydrated. Thus, there is no
need of continuing her antibiotics. The continuation of her antibiotics could also
lead to the formation of resistant bacteria.

1 8.2 E. It is essential to obtain cultures prior to starting antibiotic therapy for

presumed sepsis. Although the unnecessary use of broad-spectrum antibiotics
canlead to increased antimicrobial resistance, it is important that all bacteria are
initially covered when starting empiric antibiotic therapy. Once the bacterial
cultures return, the antibiotics can be de-escalated to the appropriate mono
therapy.
1 8.3 B. The use of broad-spectrum antibiotics for prolonged duration contributes
to the increase in antimicrobial resistance. However, their use is necessary in the
initial empiric therapy to cover the maj ority of probable pathogens. Once the
cultures have returned, the therapy can be de-escalated, so that the patient's
infection can be appropriately treated and broad-spectrum antibiotics use can be
limited. Using aseptic technique and limiting the duration of antibiotic
administration also helps reduce antimicrobial proliferation and resistance.
Chlorhexidine skin preparations have been shown to cause fewer central-line-
associated infections in comparison to povidone-iodine ( Betadine ) skin
preparations. The use of PICC in hospitalized patients has not been shown to be
associated with reduced catheter-associated infections in comparison to standard
central venous catheters.
1 8.4 A. The hyperglycemia can contribute to poor response to antimicrobial
therapy in this patient and needs to be better managed. This patient has multiple
risk factors for infection with resistant bacteria. Her wound has grown MRSA that
is sensitive to vancomycin. This is the most likely source of her sepsis. The
addition of piperacillin and tazobactam (Zosyn) does not provide additional
benefits. Her wound has been recently inspected and debrided to satisfaction,
therefore there is no indication at this time to perform an above the knee
amputation. Fungal infections are reasonably common in relatively
immunocompromised patients; however, there is no indication of this process at
this time.

1 8.5 A. This is an elderly patient who is being treated for pneumonia. Although
she is nearing the end of a standard 8-day course of antibiotics for
ventilatorassociated pneumonia, she is malnourished and still requires a
significant amount of ventilatory support. Because of her age and relative
immunecompromised status, it is reasonable to extend her antibiotics past the
standard 8 days, with re-culturing if her temperatures spike through her current
antibiotic coverage and continued vigilance for other causes of her fever.

CLINICAL PEARLS
Broad-spectrum antibiotics should be started on septic patients based on
presumed location of infection and local antibiograms
Once culture sensitivities have returned, de escalation of antibiotics should
be done to minimize the use of broad-spectrum antibiotics
The duration of antibiotic administration should be limited to specific time
courses. If there is no growth of initial cultures after 72 hours, seri ous
consideration should be given to discontinuing the antibiotics.
Prolonged administration of antibiotics may be necessary in the elderly,
immunocompromised, and clinically deteriorating patient.
Nonpharmacologic strategies for decreasing need for antibiotics in the
ICU include aseptic technique, hand-washing, and early enteral nutrition