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1

are cardinal signs of the systemic response

Fever or hypothermia, leukocytosis or leukopenia, tachypnea,
and tachycardia

2

refers to sepsis accompanied by hypotension
that cannot be corrected by the infusion of fluids

Septic shock

3

Presence of bacteria in blood, as evidenced
by positive blood cultures

Bacteremia

4

Signs of possibly harmful systemic
response

Two or more of the following conditions:

(1) fever (oral temperature >38°C [>100.4°F]) or hypothermia (<36°C [<96.8°F]);

(2) tachypnea (>24 breaths/min);

(3) tachycardia (heart rate >90 beats/min);

(4) leukocytosis (>12,000/μL), leukopenia (<4000/μL), or >10% bands

5

Sepsis (or severe sepsis)

The harmful host response to infection; systemic response to proven or suspected infection plus some degree of organ hypofunction, i.e.:

1. Cardiovascular: Arterial systolic blood pressure ≤90 mmHg or mean arterial pressure ≤70 mmHg that responds to administration of IV fluid

2. Renal: Urine output <0.5 mL/kg per hour for 1 h despite adequate fluid resuscitation

3. Respiratory: Pao2/Fio2 ≤250 or, if the lung is the only dysfunctional organ, ≤200

4. Hematologic: Platelet count <80,000/μL or 50% decrease in platelet count from highest value
recorded over previous 3 days

5. Unexplained metabolic acidosis: A pH ≤7.30 or a base deficit ≥5.0 mEq/L and a plasma lactate level >1.5 times upper limit of normal for reporting lab

6

Septic shock

Sepsis with hypotension (arterial blood pressure <90 mmHg systolic, or 40 mmHg less than patient’s normal
blood pressure) for at least 1 h despite adequate fluid resuscitation

or

Need for vasopressors to maintain systolic blood pressure ≥90 mmHg or mean arterial pressure ≥70 mmHg

7

Refractory septic shock

Septic shock that lasts for >1 h and does not respond to fluid or pressor administration

8

Fluid resuscitation is considered adequate when the

pulmonary artery wedge pressure is
≥12 mmHg or the central venous pressure is ≥8 mmHg.

9

Microbial invasion of the bloodstream is not essential
because

local inflammation can also elicit distant organ
dysfunction and hypotension

10

blood cultures yield bacteria or fungi in only

~20–40% of cases of severe sepsis and 40–70% of cases of septic shock.

11

Septic shock most common organ

Respiratory infection was most common (64%).

12

Microbiologic results were positive in 70% of individuals considered
infected; of the isolates,

62% were gram-negative bacteria
(Pseudomonas species and Escherichia coli were most common),

47% were grampositive bacteria (Staphylococcus aureus was most common)

19% were fungi (Candida species

13

Microbial pathogens, can circumvent innate defenses because they

(1) lack molecules that can be recognized by host receptors (see below) or

(2) elaborate toxins or other virulence factors.

14

A host protein (LPS-binding protein) binds lipid A and transfers the LPS to CD14 on the surfaces of monocytes, macrophages, and neutrophils. LPS then is passed to

MD-2, a small receptor protein that is bound to Toll-like receptor (TLR) 4 to form a molecular complex that transduces the LPS recognition signal to the interior of the cell.

This signal rapidly triggers the production and
release of mediators, such as tumor necrosis factor (TNF; see below), that amplify the LPS signal and transmit it to other cells and tissues.

15

NOD1 and NOD2 proteins, which
recognize discrete fragments of bacterial peptidoglycan; the inflammasome,
which senses some pathogens and produces

interleukin (IL) 1β and IL-18

16

Most of the commensal aerobic and
facultatively anaerobic gram-negative bacteria that trigger severe
sepsis and shock (including E. coli, Klebsiella, and Enterobacter) make

this lipid A structure.

17

When they invade human hosts, often through
breaks in an epithelial barrier, they are typically confined to the subepithelial
tissue by a localized inflammatory response.

Bacteremia, if
it occurs, is intermittent and low grade because these bacteria are efficiently
cleared from the bloodstream by TLR4-expressing Kupffer cells
and splenic macrophages.

These mucosal commensals seem to induce
severe sepsis most often by triggering severe local tissue inflammation
rather than by circulating within the bloodstream.

18

One exception is____
Its hexaacyl LPS seems to be shielded from host
recognition by its polysaccharide capsule.

Neisseria meningitidis.

This protection may allow
meningococci to transit undetected from the nasopharyngeal mucosa
into the bloodstream, where they can infect vascular endothelial cells
and release large amounts of endotoxin and DNA

Host recognition of
lipid A may nonetheless influence pathogenesis, as meningococci that
produce pentaacyl LPS were isolated from the blood of patients with
less severe coagulopathy than was found in patients whose isolates
produced hexaacyl lipid A; underacylated N. meningitidis LPS has
also been found in many isolates from patients with chronic meningococcemia.

19

In contrast, gram-negative bacteria that make lipid A
with fewer than six acyl chains (Yersinia pestis, Francisella tularensis,
Vibrio vulnificus, Pseudomonas aeruginosa, and Burkholderia pseudomallei,
among others) are poorly recognized by MD-2–TLR4.

When these bacteria enter the body, they may initially induce relatively little inflammation. When they do trigger severe sepsis, it is often after they
have multiplied to high density in tissues and blood.

20

Recognition
of microbial molecules by tissue phagocytes triggers the production
and/or release of numerous host molecules (cytokines, chemokines,
prostanoids, leukotrienes, and others) that

increase blood flow to the
infected tissue (rubor), enhance the permeability of local blood vessels
(tumor), recruit neutrophils and other cells to the site of infection
(calor), and elicit pain (dolor).

21

stimulates leukocytes
and vascular endothelial cells to release other cytokines (as well as
additional TNF-α), to express cell-surface molecules that enhance neutrophil
endothelial adhesion at sites of infection, and to increase prostaglandin
and leukotriene production.

TNF-α

22

Whereas blood levels of TNF-α
are not elevated in individuals with localized infections, they increase
in most patients with

severe sepsis or septic shock

Moreover, IV infusion
of TNF-α can elicit fever, tachycardia, hypotension, and other
responses. In animals, larger doses of TNF-α induce shock and death

23

Chemokines, most prominently ____ attract circulating
neutrophils to the infection site

IL-8 and IL-17

24

Exhibits many of the same activities as TNF-α.

IL-1β

25

A hallmark of the
local inflammatory response, may help wall off invading microbes and prevent infection and inflammation from spreading to other tissues.

Intravascular thrombosis,

26

When___ is expressed on
cell surfaces, it binds to factor VIIa to form an active complex that can
convert factors X and IX to their enzymatically active forms

tissue factor

The result
is activation of both extrinsic and intrinsic clotting pathways, culminating
in the generation of fibrin.

27

Clotting is also favored by impaired
function of the

protein C–protein S inhibitory pathway and depletion
of antithrombin and proteins C and S, whereas fibrinolysis is reduced
by increases in plasma levels of plasminogen activator inhibitor 1

Thus, there may be a striking propensity toward intravascular fibrin deposition, thrombosis, and bleeding; this propensity has been most apparent in patients with intravascular endothelial infections such as meningococcemia

28

is activated during sepsis but
contributes more to the development of hypotension than to that of
disseminated intravascular coagulation (DIC)

The contact system

29

are produced when neutrophils,
stimulated by microbial agonists or IL-8, release granule proteins and chromatin to form an extracellular fibrillar matrix.

Neutrophil extracellular traps (NETs)

NETs kill bacteria and fungi with antimicrobial granule proteins (e.g., elastase) and histones.

platelets can induce NET formation without killing neutrophils. A role played
by NETs in organ hypofunction during sepsis has been proposed but
not established

30

inhibit cytokine synthesis by monocytes
in vitro; the increase in blood cortisol levels that occurs early in the systemic response presumably plays a similarly inhibitory role

Glucocorticoids

31

___ inhibits the TNF-α response to endotoxin infusion in humans while augmenting and accelerating the release of IL-10;

Epinephrine

Prostaglandin
E2 has a similar “reprogramming” effect on the responses of
circulating monocytes to LPS and other bacterial agonists

32

Cortisol, epinephrine, IL-10, and C-reactive protein reduce the ability of neutrophils
to attach to vascular endothelium, favoring their

demargination
and thus contributing to leukocytosis while preventing neutrophilendothelial
adhesion in uninflamed organs

Several lines
of evidence thus suggest that the body’s neuroendocrine responses to
injury and infection normally prevent inflammation within organs distant
from a site of infection. There is also evidence that these responses
may be immunosuppressive.

33

plays important roles in the systemic compartment. Released
by many different cell types, ___ is an important stimulus to the
hypothalamic-pituitary-adrenal axis, is the major procoagulant cytokine,
and is a principal inducer of the acute-phase response, which increases
the blood concentrations of numerous molecules that have anti-infective,
procoagulant, or anti-inflammatory actions.

IL-6

34

Increased
hepatic production of___ (stimulated largely by IL-6) promotes
the sequestration of iron in hepatocytes, intestinal epithelial cells, and
erythrocytes; this effect reduces iron acquisition by invading microbes
while contributing to the normocytic, normochromic anemia associated
with inflammation.

hepcidin

35

In patients with severe sepsis, persistence of leukocyte hyporesponsiveness has been associated with an increased risk of dying; at this time, the most
predictive biomarker is

a decrease in the expression of HLA-DR (class II)
molecules on the surfaces of circulating monocytes, a response that
seems to be induced by cortisol and/or IL-10.

36

Remarkably, poorly functioning “septic” organs usually appear
normal at autopsy. There is typically very little necrosis or thrombosis,
and apoptosis is largely confined to

lymphoid organs and the gastrointestinal
tract

Moreover, organ function usually returns to normal if
patients recover. These points suggest that organ dysfunction during
severe sepsis has a basis that is principally biochemical, not structural

37

The hallmark of septic shock is a

decrease in peripheral
vascular resistance that occurs despite increased levels of vasopressor
catecholamines.

Before this vasodilatory phase, many patients experience
a period during which oxygen delivery to tissues is compromised
by myocardial depression, hypovolemia, and other factors

During this
“hypodynamic” period, the blood lactate concentration is elevated and
central venous oxygen saturation is low.

38

Fluid administration is usually
followed by the

hyperdynamic vasodilatory phase, during which
cardiac output is normal (or even high) and oxygen consumption declines despite adequate oxygen delivery

39

The blood lactate level may
be normal or increased, and normalization of central venous oxygen
saturation may reflect

improved oxygen delivery, decreased oxygen
uptake by tissues, or left-to-right shunting.

40

Prominent hypotensive molecules include

nitric oxide, β-endorphin,
bradykinin, platelet-activating factor, and prostacyclin.

41

neither a platelet-activating factor receptor antagonist nor a bradykinin
antagonist improved survival rates among patients with septic
shock,

and a nitric oxide synthase inhibitor, L-NG-methylarginine HCl,
actually increased the mortality rate.

42

In most patients infected with other gram-negative bacteria,
in contrast, circulating bacteria or bacterial molecules may reflect
uncontrolled infection at a local tissue site and have little or no direct
impact on distant organs;

in these patients, inflammatory mediators or
neural signals arising from the local site seem to be the key triggers for
severe sepsis and septic shock

43

the risk of developing severe sepsis was strongly related
to the site of primary infection: bacteremia arising from a

pulmonary
or abdominal source was eightfold more likely to be associated with
severe sepsis than was bacteremic urinary tract infection,

44

third pathogenesis may be represented by
severe sepsis due to superantigen-producing

S. aureus or Streptococcus
pyogenes; the T cell activation induced by these toxins produces a
cytokine profile that differs substantially from that elicited by gram negative
bacterial infection.

45

the absence of fever is most common in

neonates, in elderly
patients, and in persons with uremia or alcoholism.

46

Hyperventilation, producing respiratory alkalosis, is often an early sign
of the septic response.

Disorientation, confusion, and other manifestations
of encephalopathy may also develop early on, particularly in the elderly
and in individuals with preexisting neurologic impairment. Focal neurologic
signs are uncommon, although preexisting focal deficits may become
more prominent.

47

Hypotension and DIC predispose to acrocyanosis and ischemic necrosis of peripheral tissues, most commonly the digits.

Cellulitis, pustules, bullae, or hemorrhagic lesions may develop when hematogenous bacteria or fungi seed the skin or underlying soft tissue.

48

When sepsis is accompanied by cutaneous petechiae or
purpura, infection with

should be suspected

N. meningitidis (or, less commonly, H. influenzae)

in a patient who has been bitten
by a tick while in an endemic area, petechial lesions also suggest
Rocky Mountain spotted fever

49

A cutaneous lesion
seen almost exclusively in neutropenic patients is

ecthyma gangrenosum,
This bullous lesion surrounded by
edema undergoes central hemorrhage and necrosis often caused by P. aeruginosa.

Histopathologic examination shows bacteria in and around the wall of
a small vessel, with little or no neutrophilic response

50

Hemorrhagic or
bullous lesions in a septic patient who has recently eaten raw oysters
suggest

V. vulnificus bacteremia,

51

Dog bite may indicate bloodstream infection
due to

Capnocytophaga canimorsus or Capnocytophaga cynodegmi

52

Generalized erythroderma in a septic patient suggests the toxic shock
syndrome due to

S. aureus or S. pyogenes.

53

Cholestatic jaundice, with elevated
levels of serum bilirubin (mostly conjugated) and alkaline phosphatase, may precede other signs of sepsis

Hepatocellular or canalicular
dysfunction appears to underlie most cases, and the results of hepatic
function tests return to normal with resolution of the infection.

Prolonged or severe hypotension may induce acute hepatic injury or
ischemic bowel necrosis.

54

Many tissues may be unable to extract oxygen normally from the
blood, so that ___metabolism occurs despite near-normal mixed venous oxygen saturation.

anaerobic

55

levels rise early because
of increased glycolysis as well as impaired clearance of the resulting
lactate and pyruvate by the liver and kidneys

Blood lactate

56

The blood glucose
concentration often increases, particularly in patients with

diabetes,
although impaired gluconeogenesis and excessive insulin release on
occasion produce hypoglycemia.

57

The cytokine-driven acute-phase
response inhibits the synthesis of transthyretin while enhancing the
production of

C-reactive protein, fibrinogen, and complement components

58

Protein catabolism is often markedly accelerated. Serum albumin
levels decline as a result of

decreased hepatic synthesis and the movement
of albumin into interstitial spaces.

59


produces a fall in arterial Po2 early in the course

Ventilation-perfusion mismatching

Increasing alveolar
epithelial injury and capillary permeability result in increased pulmonary
water content, which decreases pulmonary compliance and interferes with oxygen exchange

60

In the absence of pneumonia or heart
failure, progressive diffuse pulmonary infiltrates and arterial hypoxemia
occurring within 1 week of a known insult indicate the development

ARDS

61

mild acute respiratory distress syndrome (ARDS)

200 mmHg < Pao2/Fio2 ≤ 300 mmHg

62

moderate ARDS

100 mmHg < Pao2/Fio2 ≤ 200 mmHg

63

severe ARDS

Pao2/Fio2 ≤100 mmHg

64

Acute lung injury or ARDS develops in

~50% of patients with severe sepsis or septic shock.

Respiratory muscle fatigue can exacerbate hypoxemia
and hypercapnia.

65

An elevated pulmonary capillary wedge pressure
suggests fluid volume overload or cardiac failure rather
than ARDS.

(>18 mmHg)

Pneumonia caused by viruses or by Pneumocystis may be clinically indistinguishable from ARDS

66

Sepsis-induced hypotension (see “Septic Shock,” above) usually
results initially from a

generalized maldistribution of blood flow and
blood volume and from hypovolemia that is due, at least in part, to
diffuse capillary leakage of intravascular fluid

67

After fluid repletion, in
contrast, cardiac output typically increases and systemic vascular resistance
falls.

Indeed, normal or increased cardiac output and decreased
systemic vascular resistance distinguish septic shock from cardiogenic extracardiac obstructive, and hypovolemic shock;

other processes that
can produce this combination include anaphylaxis, beriberi, cirrhosis,
and overdoses of nitroprusside or narcotics.

68

Depression of myocardial function, manifested as

increased end diastolic
and systolic ventricular volumes with a decreased ejection
fraction, develops within 24 h in most patients with severe sepsis.

Cardiac output is maintained despite the low ejection fraction because
ventricular dilation permits a normal stroke volume

69

In survivors, myocardial function returns to normal over several days.

Although myocardial dysfunction may contribute to hypotension, refractory hypotension is usually due to low systemic vascular resistance, and death most often results from refractory shock or the failure of multiple
organs rather than from cardiac dysfunction per se

70

Whereas a plasma cortisol level
of ≤15 μg/mL (≤10 μg/mL if the serum albumin concentration is <2.5 mg/dL) indicates adrenal insufficiency (inadequate production of
cortisol),

many experts now feel that the adrenocorticotropic hormone
(CoSyntropin®) stimulation test is not useful for detecting less profound degrees of corticosteroid deficiency in patients who are critically ill.

71

Although CIRCI may result from structural
damage to the adrenal gland, it is more commonly due to

reversible
dysfunction of the hypothalamic-pituitary axis or to tissue corticosteroid
resistance resulting from abnormalities of the glucocorticoid
receptor or increased conversion of cortisol to cortisone

72

The major
clinical manifestation of CIRCI is

hypotension that is refractory to
fluid replacement and requires pressor therapy

Some classic features of adrenal insufficiency, such as hyponatremia and hyperkalemia, are usually absent; others, such as eosinophilia and modest hypoglycemia,
may sometimes be found.

Specific etiologies include fulminant
N. meningitidis bacteremia, disseminated tuberculosis, AIDS (with
cytomegalovirus, Mycobacterium avium-intracellulare, or Histoplasma
capsulatum disease), or the prior use of drugs that diminish glucocorticoid
production, such as glucocorticoids, megestrol, etomidate, or
ketoconazole

73

Sepsis

Oliguria, azotemia, proteinuria, and nonspecific
urinary casts are frequently found.

Many patients are inappropriately
polyuric; hyperglycemia may exacerbate this tendency.

74

Most renal failure is due to

acute tubular necrosis induced by hypovolemia, arterial
hypotension, or toxic drugs, although some patients also have glomerulonephritis, renal cortical necrosis, or interstitial nephritis

75

Although thrombocytopenia occurs in 10–30% of patients, the underlying mechanisms are not understood.

Platelet counts are
usually very low (<50,000/μL) in patients with DIC; these low counts
may reflect diffuse endothelial injury or microvascular thrombosis,

76

is often
an early manifestation of sepsis. Depending on the diagnostic criteria
used, it occurs in 10–70% of septic patients at some point during the
hospital course. When the septic illness lasts for weeks or months, “critical illness” polyneuropathy may prevent weaning from ventilatory
support and produce distal motor weakness.

Delirium (acute encephalopathy)

77

Abnormalities that occur early in the septic response may include

leukocytosis with a left shift, thrombocytopenia, hyperbilirubinemia, and proteinuria.

Leukopenia may develop. The neutrophils may contain
toxic granulations, Döhle bodies, or cytoplasmic vacuoles

As the septic response becomes more severe, thrombocytopenia worsens (often with prolonged thrombin time, decreased fibrinogen, and the presence
of d-dimers, suggesting DIC), azotemia and hyperbilirubinemia become more prominent, and levels of aminotransferases rise

78

Active hemolysis suggests clostridial bacteremia, malaria, a drug reaction, or DIC;

in the case of DIC, microangiopathic changes may be seen on a blood smear.

79

During early sepsis, hyperventilation induces

respiratory alkalosis.

With respiratory muscle fatigue and the accumulation of lactate,
metabolic acidosis (with increased anion gap) typically supervenes.

Evaluation of arterial blood gases reveals hypoxemia that is initially
correctable with supplemental oxygen but whose later refractoriness
to 100% oxygen inhalation indicates right-to-left shunting

The electrocardiogram may show only sinus tachycardia or nonspecific ST–T wave abnormalities.

80

Most diabetic patients with sepsis develop

hyperglycemia.

Severe
infection may precipitate diabetic ketoacidosis that may exacerbate hypotension (Chap. 417).

Hypoglycemia occurs rarely and may indicate
adrenal insufficiency. The serum albumin level declines as sepsis continues.
Hypocalcemia is rare

81

Cultures

At least two
blood samples should be obtained (from two different venipuncture
sites) for culture;

in a patient with an indwelling catheter, one sample
should be collected from each lumen of the catheter and another via
venipuncture.

82

A large retrospective review of patients who developed septic
shock found that the interval between the onset of hypotension
and the administration of appropriate antimicrobial chemotherapy
was the major determinant of outcome;

a delay of as little as 1 h
was associated with lower survival rates

It is therefore very important to promptly initiate empirical antimicrobial
therapy that is effective against both gram-positive and
gram-negative bacteria

83

Meta-analyses have concluded that, with one exception,
combination antimicrobial therapy is not superior to monotherapy
for treating gram-negative bacteremia;

the exception is that aminoglycoside
monotherapy for P. aeruginosa bacteremia is less effective
than the combination of an aminoglycoside with an antipseudomonal
β-lactam agent.

84

Empirical antifungal therapy should be
strongly considered if

the septic patient is already receiving broadspectrum
antibiotics or parenteral nutrition, has been neutropenic
for ≥5 days, has had a long-term central venous catheter in place, or
has been hospitalized in an ICU for a prolonged period

85

Most patients require antimicrobial therapy for at least

1 week.

The duration of treatment is typically influenced by factors such as the site of tissue infection, the adequacy of surgical drainage, the patient’s underlying disease, and the antimicrobial susceptibility
of the microbial isolate(s).

86

In patients with severe sepsis
arising from the urinary tract,

sonography or CT should be used to
rule out ureteral obstruction, perinephric abscess, and renal abscess.

87

Initial management of hypotension
should include the administration of IV fluids, typically beginning
with 1–2 L of normal saline over 1–2 h.

To avoid pulmonary edema,
the central venous pressure should be maintained at 8–12 cmH2O.
The urine output rate should be kept at >0.5 mL/kg per hour by
continuing fluid administration; a diuretic such as furosemide may
be used if needed.

88

a reasonable
goal is to maintain a mean arterial blood pressure of >65 mmHg
(systolic pressure >90 mmHg). If these guidelines cannot be met
by volume infusion, vasopressor therapy is indicated

Titrated doses of norepinephrine should be administered through a
central catheter.

If myocardial dysfunction produces elevated cardiac
filling pressures and low cardiac output, inotropic therapy with
dobutamine is recommended. Dopamine is rarely used.

89

In patients with septic shock, plasma vasopressin levels increase
transiently but then decrease dramatically. Early studies found that
vasopressin infusion can reverse septic shock in some patients,
reducing or eliminating the need for catecholamine pressors.

Although vasopressin may benefit patients who require less norepinephrine,
its role in the treatment of septic shock seems to be a
minor one overall.

90

should be strongly considered
in patients who develop hypotension that does not respond
to fluid replacement therapy

CIRCI

Hydrocortisone (50 mg IV every 6 h)
should be given; if clinical improvement occurs over 24–48 h, most
experts would continue hydrocortisone therapy for 5–7 days before
slowly tapering and discontinuing it.

91

Ventilator therapy is indicated for progressive hypoxemia, hypercapnia,
neurologic deterioration, or respiratory muscle failure.

Sustained tachypnea (respiratory rate, >30 breaths/min) is frequently
a harbinger of impending respiratory collapse; mechanical ventilation
is often initiated to ensure adequate oxygenation, to divert blood
from the muscles of respiration, to prevent aspiration of oropharyngeal
contents, and to reduce the cardiac afterload

92

low tidal volumes (6 mL/kg of ideal
body weight, or as low as 4 mL/kg if the plateau pressure exceeds
30 cmH2O).

Patients undergoing mechanical ventilation require
careful sedation, with daily interruptions; elevation of the head of
the bed helps to prevent nosocomial pneumonia. Stress-ulcer prophylaxis
with a histamine H2-receptor antagonist may decrease the
risk of gastrointestinal hemorrhage in ventilated patients.

93

Erythrocyte transfusion is generally recommended when the
blood hemoglobin level decreases to

≤7 g/dL, with a target level of 9 g/dL in adults.

Erythropoietin is not used to treat sepsis-related
anemia.

Bicarbonate is sometimes administered for severe metabolic acidosis (arterial pH <7.2), but there is little evidence that it improves either hemodynamics or the response to vasopressor hormones

94

Prophylactic heparinization to prevent deep venous
thrombosis is indicated for patients who do not have active bleeding
or coagulopathy;

when heparin is contraindicated, compression stockings or an intermittent compression device should be used

95

Initial Antimicrobial Therapy for Severe Sepsis with No
Obvious Source in Adults with Normal Renal Functi on

Immunocompetent adult

The many acceptable regimens
include

(1) piperacillin-tazobactam
(3.375 g q4–6h);

(2) imipenem-cilastatin (0.5 g q6h),
ertapenem (1 g q24h),
or meropenem (1 g q8h); or

(3) cefepime (2 g q12h).

If the patient is allergic to β-lactam agents, use

ciprofloxacin (400 mg q12h) or
levofloxacin (500–750 mg q12h)

plus clindamycin (600 mg q8h).

Vancomycin (15 mg/kg q12h) should
be added to each of the above
regimens.

96

Initial Antimicrobial Therapy for Severe Sepsis with No
Obvious Source in Adults with Normal Renal Functi on


Neutropenia (<500 neutrophils/μL)

Regimens include
(1) imipenemcilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime (2 g q8h) or

(2) piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h).

Vancomycin (15 mg/kg q12h) should be added if the patient has an indwelling vascular catheter, has received quinolone prophylaxis, or has received intensive chemotherapy that produces mucosal damage;

if staphylococci are suspected; if the institution has a high incidence of MRSA infections; or if there is a high
prevalence of MRSA isolates in the community.

Empirical antifungal therapy with an echinocandin (for
caspofungin: a 70-mg loading dose, then 50 mg daily), voriconazole (6 mg/kg q12h for 2 doses, then 3 mg/
kg q12h), or a lipid formulation of amphotericin B should be added if the patient is hypotensive, has been
receiving broad-spectrum antibacterial drugs, or remains febrile 5 days after initiation of empirical antibacterial
therapy.

97

Initial Antimicrobial Therapy for Severe Sepsis with No
Obvious Source in Adults with Normal Renal Functi on


Splenectomy

Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local prevalence of cephalosporin resistant pneumococci is high, add vancomycin.

If the patient is allergic to β-lactam drugs, vancomycin
(15 mg/kg q12h) plus either moxifloxacin (400 mg q24h) or levofloxacin (750 mg q24h) should be used.

98

Initial Antimicrobial Therapy for Severe Sepsis with No
Obvious Source in Adults with Normal Renal Functi on

IV drug user

Vancomycin (15 mg/kg q12h) is
essential.

99

Initial Antimicrobial Therapy for Severe Sepsis with No
Obvious Source in Adults with Normal Renal Functi on

AIDS

Cefepime alone (2 g q8h) or piperacillintazobactam
(3.375 g q4h) plus tobramycin (5–7 mg/kg q24h) should
be used.

If the patient is allergic to β-lactam drugs, ciprofloxacin
(400 mg q12h) or levofloxacin (750 mg q12h) plus vancomycin (15 mg/kg q12h) plus tobramycin
should be used.