INFECTOUS DISEASE UPDATE
| SUPER BUGS UNLEASHED IN YOUR EMERGENCY DEPARTMENT—Peter DeBlieux, MD, Professor of Clinical
Medicine, Louisiana State University School of Medicine, New Orleans
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| Epidemiology: gram-positive sepsis has overtaken gram-negative sepsis; common gram-positive bacteria include Staphylococcus
aureus, coagulase-negative staphylococci, enterococci, and streptococci; most common gram-negative pathogens
are Escherichia coli, Klebsiella, and Pseudomonas; incidence of fungal sepsis has tripled due to transplant patients
and those on immunosuppressive therapy (accounts for only 5% of all cases of sepsis); common sites of sepsis are 1)
lungs, 2) bloodstream, 3) abdomen, 4) urinary tract, 5) skin and soft tissue; pearl—when source unknown, choose antibiotic
that covers abdominal pathogens
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| Origins of super bugs: selection of agents with broader spectrum than required; broad-spectrum antibiotics placed in animal
feed (eg, cows, sheep, chickens); patients not finishing their course of medication and giving leftover pills to friends
or relatives; propensity of physicians to overuse antibiotics (medicate rather than educate); selection pressure number one
etiology of resistance, ie, sensitive organisms killed by antibiotic, resistant organisms multiply
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| Case: 3-yr-old presents with temperature of 39.5°C (103°F), photophobia, mastoid tenderness, and confusion; enrolled in
day care (other high-risk environments include pediatric emergency department [ED] and nursing homes); 2-day history
of malaise; recently treated for otitis media with amoxicillin (Amoxil) for 10 days; white blood cells (WBCs)
22,000/mm3 with left shift; computed tomography (CT) of head normal; lumbar puncture (LP) shows Streptococcus
pneumoniae; chest x-ray shows infiltrate in left lower lobe
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 | Discussion: 30% incidence of penicillin-resistant S pneumoniae (vancomycin current treatment of choice); Infectious
Disease Society of America recommends adding vancomycin to ceftriaxone (Rocephin) therapy if S pneumoniae
strongly suspected or if patient severely ill
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| S pneumoniae impact and resistance: >3000 cases of meningitis, >50,000 cases of bacteremia, >500,000 cases of pneumonia,
7 million cases of otitis media; risk factors—patients >65 yr of age; treatment with β-lactam or other antibiotic
therapy within last 3 mo (ask routinely before prescribing any antibiotic); alcoholism; immunosuppression; multiple
medical comorbidities; exposure to child care or day care environment; organisms for which minimal inhibitory concentration
(MIC) of penicillin ≤0.06 µg/mL considered susceptible; MIC between 0.12 µg/mL and 1.0 µg/mL considered intermediate;
MIC >2 µg/mL considered resistant (based on meningitis; MIC 4-8 µg/mL for pneumonia); if high-level
resistance present, consider vancomycin as additional therapy in meningitis; susceptible or intermediate strains treated
with higher doses of penicillin; MIC >2 µg/mL indicates cross-resistance to erythromycin, cephalosporins, ciprofloxacin,
and tetracycline; in vitro data do not translate to in vivo data; alteration in penicillin-binding proteins mechanism of resistance
for penicillin-resistant S pneumoniae (considered low-level mechanism); for macrolides, mechanism involves efflux
pump; for ciprofloxacin, mechanism involves DNA gyrase; for extended-spectrum fluoroquinolones, mechanism involves
DNA gyrase plus topoisomerase
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| Community-acquired urinary tract infections (UTIs): 75% to 90% caused by E coli, 10% to 20% by Staphylococcus
saprophyticus, <5% by Proteus mirabilis, Klebsiella, and enterococcus; if patient has been instrumented, been in nursing
home, has indwelling Foley catheter or stent placed recently, incidence of E coli plummets and other complicated
gram-negative organisms skyrocket; overall resistance to multiple antibiotics, including penicillins, cephalosporins and
sulfonamides has doubled from 9% to 18%; “you need to know what’s going on within your community to make the right
choices for your patient population”; surveillance data within hospital, city, county, and state essential; risk factors for
community resistance to trimethoprim–sulfamethoxazole (Bactrim, Septra) include recent hospitalization, presence of diabetes,
≥3 UTIs within past year (these patients high-risk and should never receive trimethoprim–sulfamethoxazole therapy);
E coli—most common cause of gram-negative nosocomial infections and most common organism in nosocomial
UTI; hospital E coli much more virulent than community strains and have different mechanism of resistance
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| Methicillin-resistant S aureus (MRSA) epidemiology: 40% of total hospital S aureus infections; vancomycin current
treatment of choice for nosocomial MRSA; S aureus most common cause of nosocomial skin and wound infections;
within hospital, MRSA incidence 30% to 40% in 1990s, 57% in 2002 and growing exponentially; S aureus in hospital
presumed to be MRSA until proven otherwise
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| Risk factors for MRSA: age >60 yr; prolonged hospitalization in transferred patients; central venous access; urinary catheter;
recent history of hospitalization, surgery or antibiotic therapy; presence of open skin lesions
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| Community-acquired MRSA: hospital-acquired MRSA different from community-acquired MRSA, ie, has different genetics,
sensitivities, and treatments; incision and drainage remains treatment for MRSA skin abscess; abscess with >2
cm of surrounding erythema considered cellulitis and should be treated with antibiotics; outpatient treatment still cephalexin;
may use Bactrim, but no data that Bactrim superior to cephalexin; can add rifampin to Bactrim therapy, but
never use rifampin alone; dicloxacillin also used; risk factors include recent antibiotic use, sharing contaminated items,
active skin diseases, living in crowded settings
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| Hospital-acquired MRSA: generally resistant to β-lactam agents, fluoroquinolones, macrolides, aminoglycosides; mechanism
is alteration in penicillin-binding proteins; vancomycin indicated
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| Methicillin-resistant Staphylococcus epidermidis (MRSE): most common pathogen in line infections; produces slime that
adheres to central venous catheter; vancomycin therapy indicated
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| Case: 74-yr-old nursing home patient presents with history of end-stage renal disease with temperature of 38.5°C (101°F)
and generalized weakness; receives hemodialysis Monday, Wednesday, Friday and receives vancomycin with each session
of dialysis; blood urea nirtogen (BUN) 120 mg/dL, creatinine 4.5 mg/kg per 24 hr, WBC 17,000 /mm3 with left
shift, electrocardiography (ECG) unchanged from previous
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| Enterococcal resistance: vancomycin-resistant enterococcus (VRE) >7% and growing; prolonged hospitalization with
multiple-antibiotic therapy ideal for fostering VRE; patients become colonized with VRE, and cross-contamination likely
when these patients cared for in ED; VRE patients require one-on-one nursing care; multiresistant strains caused by gene
transfer (epidemic potential); ampicillin and gentamicin current treatment regime; pearl—all systemic enterococcal infections
require ampicillin and gentamicin; mechanism of resistance—alteration of penicillin-binding proteins and impermeability
of bacterial cell wall; risk factors for VRE—include prolonged hospitalization, immunocompromised host,
neutropenia, previous vancomycin or cephalosporin use, renal failure, and intensive care unit (ICU) admission
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| INSIGHTS FROM THE SURVIVING SEPSIS CAMPAIGN—Jay L. Falk, MD, Clinical Professor of Medicine and Emergency
Medicine, University of Florida College of Medicine, Gainesville, Academic Chairman, Department of Emergency
Medicine, Orlando Regional Medical Center, and Chief, Academic Medical Officer, Orlando Regional Healthcare
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| Introduction: early goal-directed therapy (EGDT) in critically ill septic patient “concept whose time has come”; important to
start therapy in ED and make smooth transition into critical care unit (CCU; have not achieved this for septic patients); sepsis
should be in same category as heart attack, trauma, and stroke
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| Surviving sepsis campaign guidelines: endorsed by 11 societies throughout world, including American College of Emergency
Physicians (ACEP); guidelines published in February 2004 in Critical Care Medicine
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| What is sepsis? infection, documented or suspected, plus some marker of systemic inflammation; systemic inflammatory
response syndrome (SIRS); severe sepsis complicated by organ dysfunction; septic shock is state of circulatory failure
with persistent hypotension unexplained by other causes; infection activates proinflammatory cytokines that mount modulated
response to isolate, combat, and resolve infection; however, in some cases, prolonged unmodulated response results
in multiple organ dysfunction, septic shock, and possibly death; at present, cannot predict which type of response
will occur
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| New insights on sepsis cascade: endothelium can cause increase in intravascular coagulation and decrease in fibrinolysis;
endothelial inflammation contributes to downward spiral leading to organ failure and death
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| Recombinant human activated protein C (Xigris) study: randomized, double-blind, placebo-controlled trial of 164
centers in 11 countries; inclusion criteria were clinical infection with inflammation and organ dysfunction; patients presented
primarily with pneumonia and gram-positive organisms; over 28 days, mortality 30% in placebo group, 24.7% in
Xigris group; one life saved for every 16 patients treated; surviving sepsis campaign guidelines recommend giving Xigris
to patients at high risk for death (category B recommendation); candidates should have Acute Physiology and Chronic
Health Evaluation (APACHE) II scores >25, multiple organ failure, septic shock or acute respiratory distress syndrome
(ARDS), and no contraindications (eg, risk of bleeding); in some institutions, use restricted to infectious disease consultants
and intensivists; several studies currently investigating administration in ED to see whether earlier administration
improves outcomes
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| Diagnosis: culture all potential sources in ED (one from peripheral site, and one from lumen of each indwelling catheter);
perform diagnostic studies to look for source of infection; confirm site and/or positive blood culture (≈50% of patients in
septic shock have negative blood cultures; fraction of patients with no apparent site of infection have positive blood cultures)
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| Therapy: mortality doubled if first antibiotic regimen given does not cover causative organism; failure to give antibiotics
in timely fashion common cause of litigation; give broad-spectrum antibiotics appropriate for suspected organisms, site,
and resistance patterns in community; use full loading dose; Pseudomonas infections and neutropenic patients need combination
therapy; stop antibiotics early if no site of infection found; drain, debride, and remove infected sources (patients
never too sick to have pus drained); do not hesitate to call surgeon early; perform percutaneous drainage of abscesses
early to stabilize patient, then definitive procedure later; surgical procedure and removal of potentially infected lines indicated
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| Types of deficits in O2 delivery: hypoxic hypoxia (low PaO2 ); anemic hypoxia (low hemoglobin); stagnant hypoxia (low
cardiac output); cytopathic hypoxia (cell machinery unable to utilize O2 ); patients need not have hypotension, ie, poor perfusion
may be caused by shunting or vasodilator-enhanced perfusion (warm shock; vascular beds in skin dilated while
splanchnic beds constricted), leading to “metabolic block”; lactate effective tool for predicting mortality (50% mortality
with lactate of 5 mmol/L)
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| Goals of fluid resuscitation: restore plasma volume to augment preload and increase output, delivery, and O2 consumption
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| Colloid vs crystalloid controversy: many studies flawed; most recent study showed no difference in mortality and other
outcomes, eg, development of ARDS; takes more crystalloid to reach required end point, hence crystalloids cause more
edema
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| Inotropic therapy: if monitored metabolic end points indicate patient has perfusion problems, dobutamine inotropic therapy
of choice after fluid resuscitation; add pressor if patient hypotensive
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| EGDT in severe sepsis: randomized prospective blinded study; 263 patients entered in ED with SIRS and either hypotension
or lactate >4 mmol/L; patients received standard therapy or EGDT for 6 hr, followed by usual intensive care unit
(ICU) care with team blinded to which therapy given in ED
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| Case example: 32-yr-old man with history of throat cancer metastatic to brain and cardiac arrest 1 mo ago; coughing last
few days; febrile, tachycardic, normotensive, tachypneic; saturations 97%; WBC 7000/mm3 with 33% bands; lactate 7
mmol/L; has enterococcus in urine and Pseudomonas in sputum; mixed central venous saturation 67% (normal 75%)
after first 3 L of fluid
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| Application of EGDT: give supplemental O2 or intubate (at clinician’s discretion); central venous catheterization with
continuous monitoring indicated; use fluid boluses to increase central venous pressure (CVP) to 8 to 12 mm Hg; if
mean arterial pressure (MAP) still <65 mm Hg, use pressor to get it up to 65 mm Hg; if very high, use vasodilator to reduce
pressure to proper range; if central venous saturation <70% after pressure and volume corrected, check hematocrit;
if hematocrit <30%, transfuse red blood cells (RBCs); if hematocrit ≥30% use inotropic agent to increase O2
delivery and check saturation
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| EGDT vs standard therapy: no differences at baseline; during first 6 hr, EGDT group received more fluid, RBCs, and
dobutamine but about same amount of pressors as standard-therapy group; mortality almost 50% in standard-therapy
group, 30% in EGDT group; need to treat 6 to 8 patients with EGDT to prevent 1 death (18% reduction in mortality); sudden
cardiovascular collapse twice as high in standard-therapy group as with EGDT
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| New protocol guidelines for EGDT: initial resuscitation in ED should include early recognition of patients with occult
shock (low blood pressure or high lactate); must look at systemic hypoperfusion; initiate EGDT at time sepsis identified,
ie, give fluids, check MAP, urine output, and mixed venous saturation; after fluids administered, use pressors to keep
MAP at 65 mm Hg; low-dose steroids (100 mg tid) also reduce mortality; use steroids in vasopressor-dependent patients
(eg, hydrocortisone 200-300 mg/day for 7 days; unmasks occult adrenal insufficiency); do not use high-dose steroids (eg,
3.5 g methylprednisolone)
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Educational Objectives
| The goal of this program is to educate the listener about antibiotic resistance and management of sepsis. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Describe the epidemiology of drug-resistant organisms.
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| 2. Name the environments that are high-risk for acqusition of Streptococcus pneumoniae.
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| 3. List the risk factors for methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus
epidermidis.
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| 4. Define sepsis.
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| 5. Describe the new guidelines for early goal-directed therapy for the treatment of sepsis.
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Discussed On This Program
Amoxicillin [Amoxil, Trimox]
Ampicillin [Principen]
Ampicillin sodium and sulbactam sodium [Unasyn]
Ceftriaxone sodium [Rocephin]
Ciprofloxacin [Ciloxan, Cipro, Proquin XR]
Daptomycin [Cubicin]
Dobutamine [Dobutrex]
Drotrecogin alfa (activated protein C) [Xigris]
Erythromycin (many trade names)
Gentamicin sulfate (many trade names)
Hydrochlorothiazide (many trade names)
Hydrocortisone (cortisol) (many trade names)
Imipenem-cilastatin [Primaxin I.M., Primaxin I.V.]
Linezolid [Zyvox]
Methylprednisolone [Medrol]
Penicillin (many trade names and formulations)
Quinupristin/dalfopristin [Synercid]
Rifampin (rifampicin) [Rifadin, Rimactane]
Tetracycline HCl (Sumycin)
Ticarcillin and clavulanate potassium [Timentin]
Trimethoprim-sulfamethoxazole (co-trimoxazole; TMP-SMZ) [Bactrim, others]
Vancomycin [Vancocin, Vancoled]
Programs of Related Interest
Long SS, O’Hara C: Infectious disease update. Audio-Digest Pediatrics 50:17(Sep 7), 2004; Moran GJ, Avner JR: Infectious
emergencies. Audio-Digest Emergency Medicine 21:06(Mar 21), 2004; Sande MA: Emerging infectious disease
disasters. Audio-Digest Internal Medicine 52:10(May 21), 2005; Zydowicz DA et al: Infectious disease: concerns and
prevention. Audio-Digest Family Practice 53:18(May 14), 2005.
To Order, Contact Subscriber Service (1-800-423-2308)
Suggested Reading
Angus DC et al: The effect of drotrecogin alfa (activated) long-term survival after severe sepsis. Crit Care Med 32:2199,
2004; Ely EW et al: Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe
sepsis. Crit Care Med 31:12, 2003; Fourrier F: Recombinant human activated protein C in the treatment of severe
sepsis: an evidence-based review. Crit Care Med 32:S534, 2004 (Erratum 33:2157, 2005); Frazee BW et al: High prevalence
of methicillin-resistant Staphylococcus aureus in emergency department skin and soft tissue infections. Ann Emerg
Med 45:311, 2005; Grant DC et al: Urine nitrite not correlated with bacterial resistance to cephalosporins. J Emerg Med
28:321, 2005; Gunn SR et al: Equipment review: the success of early goal-directed therapy for septic shock prompts evaluation
of current approaches for monitoring the adequacy of resuscitation. Crit Care 9:349, 2005; Keh D et al: Use of corticosteroid
therapy in patients with sepsis and septic shock: an evidence-based review. Crit Care Med 32:S527, 2004;
Kunsdorf-Wnuk A et al: The use of recombinant human activated protein C (rhAPC) in the treatment of severe sepsis in
immunosuppressed patients in the course of hematological diseases. Med Sci Monit 11:CS49, 2005; Lee TA et al: Three
surveillance strategies for vancomycin-resistant enterococci in hospitalized patients: detection of colonization efficiency
and a cost-effectiveness model. Infect Control Hosp Epidemiol 26:39, 2005; Meisner M: Biomarkers of sepsis: clinically
useful? Curr Opin Crit Care 11:473, 2005; Moran GJ: New directions in antiinfective therapy for community-acquired
pneumonia in the emergency department. Pharmacotherapy 21:95S, 2001; Osborn TM et al: Emergency medicine and
the surviving sepsis campaign: an international approach to managing severe sepsis and septic shock. Ann Emerg Med
46:228, 2005; Schulz P et al: Infections due to community-acquired methicillin-resistant Staphylococcus aureus: an emergent
epidemic in Kentucky. J Ky Med Assoc 103:194, 2005; Shapiro NI et al: A blueprint for a sepsis protocol. Acad
Emerg Med 12:352, 2005; Vincent JL et al: Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS
trial. Crit Care Med 31:834, 2003; Yinnon AM et al: Analysis of 5 years of bacteraemias: importance of stratification of
microbial susceptibilities by source of patients. J Infect 35:17, 1997.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, Dr. Falk discloses
relationships with Eli Lilly & Company and Edwards Pharmaceuticals.
Dr. DeBlieux was recorded February 18, 2005 in San Diego, at the 11th Annual Scientific Assembly, sponsored by the
American Academy of Emergency Medicine (AAEM); Dr. Falk, February 24, 2005, in Orlando, Florida, at Emergency
Medicine for the Critically Ill and Injured, sponsored by Orlando Regional Healthcare. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
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