Sepsis and Septic Shock: Selection

of Empiric Antimicrobial Therapy

Burke A. Cunha, MD, MACP
a,b,
*
a
Infectious Disease Division, Winthrop-University Hospital, Mineola,
NY 11501, USA
b
State University of New York School of Medicine, Stony Brook, New York, USA
Sepsis is bacteremia accompanied by fever with or without hypotension.
Bacteremia may not be demonstrable if blood cultures are obtained late in
the septic process or if the patient has received prior antibiotic therapy. Sep-
tic shock is sepsis with hepatic or renal dysfunction accompanied by pro-
found hypotension. Bacteremia is the essential and fundamental
pathophysiological determinant of sepsis. In patients who have sepsis, bac-
teremia should be assumed if not demonstrated by stained buy coat smears
or blood cultures. Host defenses are designed to prevent sepsis and septic
shock from occurring. For sepsis to occur, a large bacterial inoculum
must breach host defenses. The most common conditions associated with
sepsis include central venous catheter (CVC) infections, intravascular infec-
tions, hepatobiliary infections, colon and pelvic infections, and urosepsis.
Empiric antimicrobial therapy of sepsis depends upon localizing the site
of infection to a particular organ, which determines the pathogenic ora
in the septic process. The usual pathogens are determined by the organ or
infection site, are predictable, and are the basis for the selection of appropri-
ate empiric antimicrobial therapy. Antibiotics selected for sepsis should
have a low resistance potential, few adverse eects, and a high degree of ac-
tivity against the presumed pathogens based upon site of infection.
Sepsis may be mimicked clinically and hemodynamically by a variety of
medical disorders. Before instituting empiric antimicrobial therapy for pre-
sumed sepsis, the clinician should, on the basis of history, physical examina-
tion, and routine laboratory tests, rule out the medical disorders that mimic
sepsis. The common medical mimics of sepsis include acute pulmonary
* Infectious Disease Division, Winthrop-University Hospital, 259 First Street, Mineola,
NY 11501.
0749-0704/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2007.12.015 criticalcare.theclinics.com
Crit Care Clin 24 (2008) 313334
infarction and embolism, acute myocardial infarction, acute gastrointestinal
hemorrhage, acute edematous or necrotic pancreatitis, overzealous antidiu-
retic therapy, and relative adrenal insuciency in patients on chronic steroid
therapy. Because each of these medical disorders are potentially life-threat-
ening, an early accurate diagnosis is important to begin appropriate therapy
for the medical disorder mimicking sepsis.
Sepsis and septic shock have dierent denitions and represent a spec-
trum of clinical presentations. Sepsis is the presumptive diagnostic term
for fever associated with bacteremia with or without hypotension. Bacter-
emia may not be present if blood cultures are obtained late in the septic
process. Septic shock is sepsis with mild or moderate hepatic renal dys-
function accompanied by profound hypotension. Previously, as anticyto-
kine therapies for sepsis were being developed, the denition of sepsis
was broadened to include more patients for study purposes. However,
this denition excluded bacteremia as a necessary requisite for the diagno-
sis. While blood cultures in a patient with sepsis may be negative for a va-
riety of reasons (ie, suboptimal timing, inadequate volume of blood, prior
antibiotic treatment), bacteremia is nonetheless the essential and funda-
mental pathophysiological determinant of sepsis. Even if blood cultures
are negative for one of the aforementioned reasons, every eort should
be to demonstrate bacteremia in patients being diagnosed with sepsis.
In sepsis, bacteremia should be demonstrated by stained buy coat smears
or blood cultures or assumed to be present [18].
Because sepsis is the result of a severe bacterial infection, empiric anti-
biotic therapy is directed against the presumed and usual bacterial patho-
gens determined by the organ infected. Empiric antimicrobial therapy
should be highly eective against the presumed pathogen or pathogens
and should be administered as early as possible. For antimicrobial therapy
to be eective, other supportive measures (eg, volume replacement) must be
of the correct type and volume, and must be given early in the septic pro-
cess before pressors are given. Otherwise, volume replacement given after
pressors is ineective and will not result in restoring adequate intravascular
volume [9,10].
Sources of sepsis
Overview
Host defenses are designed to prevent sepsis. Thus, for sepsis to occur,
a large bacterial inoculum must breach and overwhelm host defenses.
Gram-positive sepsis is most commonly caused by staphylococci or entero-
cocci whereas gram-negative sepsis is caused by aerobic gram-negative ba-
cilli (GNBs). Gram-positive cocci originate from skin. Enterococci and
GNBs are from the gastrointestinal or genitourinary tracts [4,9].
314 CUNHA
Sepsis sources: central venous catheters
For CVC sepsis, coverage should be directed against Staphylococcus
aureus. If methicillin-sensitive S aureus (MSSA) strains predominate in an
institution, antimethicillin-resistant S aureus (anti-MRSA) is not necessary
after catheter removal. In critically ill patients, the CVC can be safely
removed and sent for CVC semiquantitative tip culture and a new CVC
can be replaced over the guidewire until the removed CVC tip results are re-
ported. If the CVC tip cultures are negative (ie, %15 colonies), the new CVC
should remain in place. Conversely, if the CVC tip results are positive (ie,
R15 colonies), the new CVC should be removed and another CVC inserted
at a dierent site [1116].
The clinical syndrome of sepsis occurs in few settings. Central intrave-
nous line infections are, in the main, caused by staphylococci. CVC breaches
the normal skin barrier to infection and bacteria may be directly introduced
into the bloodstream and if present in sucient numbers will result in clin-
ical sepsis. Since MSSA/MRSA or aerobic GNBs are common pathogens in
CVC infections, empiric coverage should include anti-MSSA and should
provide and GNB activity for presumed CVC infection (eg, meropenem if
MSSAO MRSA in CVC in hospital) covers both MSSA aerobic GNBs.
In hospitals where MRSA is more prevalent than MSSA as a cause of
CVC line infections, tigecycline provides empiric monotherapy against
both MRSA and most aerobic GNBs. Regardless of the presumed patho-
gens in CVC-related infections, the primary therapeutic intervention is
CVC removal [14,16].
Sepsis sources: genitourinary tract
Urosepsis is sepsis originating from the urinary tract, where the organism
cultured from the urine is the same as the organism cultured from the blood.
The urinary tract, like other organ systems, is designed to prevent infection.
Urosepsis occurs only in the setting of pre-existing renal disease, abnormal
urinary tract anatomy, foreign bodies (stents), renal or bladder stones, or
genitourinary instrumentation with infected urine. Uropathogens causing
urosepsis originate from the gastrointestinal tract and expectedly are aerobic
GNBs or group D enterococci, usually Enteroccoccus faecalis (ie, vancomy-
cin-sensitive enterococci [VSE]) [1719].
Sepsis sources: gastrointestinaI tract
Another important source of sepsis is the distal gastrointestinal tract. The
colon contains more bacteria than any other organ. The fecal ora is pre-
dominantly (w75%) Bacteroides fragilis. Most of the remaining anaerobic
fecal ora are common coliforms (w20%) and less common aerobic
GNBs, excluding Pseudomonas aeruginosa. The remaining portion of fecal
ora (w5%) is comprised of group D enterococci. Of this, about 95% are
315 SEPSIS & SEPTIC SHOCK
E faecalis (VSE) and about 5% are Enterococcus faecium, which are virtu-
ally all vancomycin resistant (VRE). Because group D enterococci are per-
missive pathogens in the gastrointestinal tract (excluding the biliary tract),
specic anti-VSE coverage is unnecessary in intra-abdominal infections
[4,8,10,20].
Biliary tract sepsis is usually due to Escherichia coli, Klebsiella pneumo-
niae, or VSE. Optimal empiric monotherapy is with meropenem, piperacil-
lin-tazobactam, levooxacin, or tigecycline [10,20].
Sepsis of colonic or pelvic origin requires antiaerobic GNB coverage (ie,
coliforms) plus antibiotic antianaerobic (ie, B fragilis) coverage. Coverage
against VSE, the permissive pathogen of the abdomen (excluding the bil-
iary and urinary tract), is not needed. Sepsis of hepatic origin should be ap-
proached the same as sepsis for the lower abdomen and pelvis because the
portal blood supply is derived from the colon [35].
Clinicians should endeavor to localize the probable source of sepsis by
history, physical examination, and routine laboratory tests to determine or-
gan-appropriate empiric antibiotic therapy [8,9]. For community-acquired
urosepsis, empiric coverage should provide coverage against aerobic
GNBs and VSE. When hospital-acquired urosepsis is related to urologic in-
strumentation procedures, antiP aeruginosa coverage should be provided.
As with CVC line infections, if urosepsis is due to obstruction, stone, foreign
body (stent), or renal abscess, surgical intervention is usually necessary to
control and eliminate the infection. For coverage of community-acquired
or nosocomial urosepsis, piperacillin-tazobactam, levooxacin, or merope-
nem provide optimal monotherapy [8,21].
Sepsis sources: pulmonary
With a few notable exceptions, pneumonias are not associated with sep-
sis or septic shock. Pneumonias may be classied in many ways by causa-
tive organism or by site of acquisition (ie, community-acquired pneumonias
[CAPs] or nosocomial pneumonia [NP]. A subset of hospital-acquired
pneumonia (HAP) or NP is ventilator-associated pneumonia (VAP).
From the infectious disease perspective, NP, HAP, and VAP are caused
by the same pathogens, have the same clinical presentation, and require
the same approach to empiric antimicrobial therapy. Occasionally, patients
with HAP, NP, or VAP may be complicated by septic shock. There are
three NP, HAP, and VAP pathogens that have the potential to cause sepsis
and septic shock. These are K pneumoniae, S aureus, and P aeruginosa. K
pneumoniae, S aureus, and P aeruginosa NPs are each characterized by
high spiking fevers, cyanosis, hypotension, and rapid cavitation on chest
radiograph. Necrotizing cavitary pneumonias, S aureus (MSSA or
MRSA), and P aeruginosa are characterized by rapid cavitation on radio-
graph within 72 hours after clinical onset. The cavitation associated with K
pneumoniae typically occurs within 3 to 5 days after onset. Hemorrhagic
316 CUNHA
cavitary pneumonia is a characteristic feature of MSSA and MRSA pneu-
monias including inuenza related MSSA/MRSA CAPs. The absence of
rapid cavitation and hemorrhagic necrotic pneumonia without high spiking
fevers, cyanosis, or hypotension argues against the diagnosis of community
or nosocomial acquired staphylococcal pneumonia. Although a quarter to
a third of ventilated patients in intensive care units have MSSA or MRSA
colonization of respiratory secretions, MSSA and MRSA NP remains
a distinctive and uncommon clinical entity. In the authors experience,
nosocomial staphylococcal pneumonias are very uncommon with no
more than one or two cases encountered per year.
CAPs are not associated with sepsis or septic shock except in three
circumstances. Firstly, K pneumoniae is seen virtually only in chronic alco-
holics. K pneumoniae CAP is similar to K pneumoniae NP in terms of its clin-
ical characteristics and radiograph appearance. Nosocomial K pneumoniae is
more likely to present with sepsis and shock then its community-acquired
counterpart. P aeruginosa is not a cause of CAP except in patients with cys-
tic brosis or chronic bronchiectasis and even in these patients does not
present with sepsis or septic shock. Patients who have febrile neutropenia
who are predisposed to Pseudomonas bacteremia do not present with Pseu-
domonas pneumonia with sepsis or septic shock.
CAP due to MSSA or MRSA, either community-onset MRSA (CO-
MRSA) or community-acquired MRSA (CA-MRSA), may present with
sepsis and shock in patients with viral inuenza or an inuenzalike ill-
ness. Most staphylococcal pneumonias seen in the hospital are commu-
nity acquired and superimposed upon viral inuenza. In the absence of
inuenza, S aureus is rarely, if ever, a CAP pathogen. Viral inuenza
with associated tracheo-bronchial damage predispose to necrotizing hem-
orrhagic MSSA and MRSA CAP. Viral inuenza alone is associated
with a high mortality and morbidity even in young healthy adults. Cer-
tainly patients with viral inuenza and superimposed MSSA or MRSA
pneumonia are critically ill. However, it is dicult to factor out the rel-
ative contributions of the bacterial versus the viral component in terms
of its virulence potential which, if not synergistic, is certainly additive
[2126].
Septic sources: impaired splenic function
Overwhelming pneumococcal sepsis occurs in patients with asplenia or
diminished splenic function. Such patients usually present with overwhelm-
ing pneumococcal sepsis rather than pneumococcal pneumonia even if the
initial site of infection is the lungs or upper respiratory tract. Patients
who have overwhelming pneumococcal sepsis, unlike those who have other
pneumonias, present with a diuse petechial or ecchymotic rash and shock
at the outset so that the Roentgen manifestations of pneumonia usually
have no time to develop [23,2731].
317 SEPSIS & SEPTIC SHOCK
Septic sources: skin and soft tissue
Uncomplicated skin and soft-tissue infections are rare causes of sepsis
and septic shock, but sepsis may result from complicated skin and skin-
structure infections. Important exceptions include toxic shock syndrome
(TSS) due to TSS-Iproducing strains of group A streptococci or
S aureus. TSS is characterized by multiorgan dysfunction and may be fatal,
but TSS is primarily a toxin-mediated disorder rather than a septic process
per se. Necrotizing fasciitis may be accompanied by sepsis and septic shock
if untreated. Necrotizing fasciitis may be complicated by TSS when due to
group A streptocci or S aureus [3235].
Community acquired methicillin-resistant Staphylococcus aureus
A newly recognized cause of sepsis and sepsis shock related to skin and
soft-tissue infections is that of the severe necrotizing pyodermas caused by
CA-MRSA. CA-MRSA may be associated with a highly virulent gene, the
PVL gene. CA-MRSA strains may be PVL positive or negative. Commu-
nity-acquired PVL-negative strains resemble in their clinical presentation
and severity MSSA, HA-MRSA, or CO-MRSA. However, CA-MRSA
strains that are PVL positive typically present as severe necrotizing pyo-
dermas out of proportion to the severity of the initial trauma or trauma
at the site of infection. While CA-MRSA strains may be susceptible to clin-
damycin, trimethoprim-sulfamethoxazole (TMP-SMX), or doxycycline, it is
prudent to treat all MRSA strains (ie, HA-MRSA, CO-MRSA, and CA-
MRSA), including both PVL-positive and PVL-negative strains, with anti-
biotics that are known to have activity against HA-MRSA. Do not rely on
in vitro susceptibility testing to treat MRSA infections. There is often a dis-
crepancy between in vitro susceptibility and in vivo eectiveness clinically.
Typically, some MRSA strains appear to be susceptible to quinolones or
cephalosporins by in vitro susceptibility testing, but these drugs are ineec-
tive in vivo. Therefore, when confronted with a patient with sepsis or septic
shock due to MRSA, it is prudent to use one of the anti-MRSA drugs (ie,
vancomycin, daptomycin, linezolid, or tigecycline) that have proven clinical
ecacy. A major clinical mistake is to assume that all MRSA infections
admitted from the community are CA-MRSA infections.
Virtually all patients presenting to hospitals from the community with
MRSA have CO-MRSA rather than CA-MRSA. CA-MRSA, both
PVL-positive and PVL-negative, presents only as one of two clinical
syndromesdas severe necrotizing pyodermas or as necrotizing CAP in
patients with inuenza or inuenzalike illnesses. Patients presenting from
the community with MRSA without either of these clinical syndromes
should be assumed to have CO-MRSA and treated accordingly. Patients
with HA-MRSA or CO-MRSA do not respond to CA-MRSA antibiotics
(ie, doxycycline, clindamycin, or TMP-SMX). Therefore, all patients pre-
senting from the community with MRSA infections, unless they present
318 CUNHA
with severe necrotizing pyodermas or staphylococcal CAP with inuenza,
should be treated as CO-MRSA strains with one of the agents listed above
[25,26].
Clostridial myonecrosis
Gas gangrene is the other skin and soft-tissue infection that may resemble
sepsis or septic shock. Gas gangrene is primarily a toxin-mediated disease
with clinical manifestations related to clostridial exotoxins. For this reason,
there is little fever associated with gas gangrene and the treatment of gas
gangrene (ie, clostridial myonecrosis) is primarily surgical to remove devital-
ized tissue.
Septic sources: bones and joints
Skin and soft-tissue infections, including septic arthritis and osteomyeli-
tis, are ordinarily not accompanied by sepsis or septic shock. Complicated
skin and soft-tissue infections in compromised hosts, such as patients with
diabetes mellitus, may present with sepsis or septic shock (Table 1) [13,32].
Mimics of sepsis: medical mimics of the acute surgical abdomen
Several conditions may present withacute abdominal pain accompaniedby
fever, leukocytosis, and hypotension, mimicking intra-abdominal sepsis.
These medical disorders include diabetic crisis in diabetic patients who
have ketoacidosis, a luetic crisis in patients who have syphilis, right-rectus
syndrome in patients who have Epstein-Barr virus infectious mononucleosis,
rectus sheath hematoma, acute porphyria, systemic lupus erythematosus
(SLE) are involving the peritoneum, acalculous cholecystitis (due to vascu-
litis [eg, SLE, polyarteritis nodosa]), dissecting abdominal aortic aneurysm,
splenic rupture (from any cause), and pseudoappendicitis due to Yersinia en-
terocolitica or other organisms. These medical mimics of acute intra-abdom-
inal sepsis are serious disorders, many of which have specic treatments. As in
ruling out the other causes of pseudosepsis, clinicians should endeavor to ar-
rive at the correct diagnosis because each disorder mimicking sepsis requires
a dierent therapeutic approach. If the diagnosis of the medical mimics of the
acute abdomen is not clear at the time of presentation by history, physical ex-
amination, or routine laboratory tests, then empiric antimicrobial therapy is
unnecessary, but not unreasonable (Box 1) [3643].
Sepsis: acute surgical abdomen
The upper gastrointestinal tract has relatively low numbers of aerobic
GNBs, which is why perforation to the upper gastrointestinal tract does
not ordinarily result in sepsis. The colon, in contrast, has more bacteria
319 SEPSIS & SEPTIC SHOCK
Table 1
Clinical conditions associated with sepsis and nonseptic disorders
Source condition, disorder, or device
Source area Associated with sepsis Not associated with sepsis
Gastrointestinal tract Liver abscess Esophagitis
Gallbladder wall abscess Gastritis
Cholangitis Pancreatitis
Colon perforation Gastrointestinal bleeding
Colitis
Diverticulitis
Toxic megacolon
Abscess
Genitourinary tract Renal or bladder calculi Urethritis
Pyelonephritis Cystitis (normal hosts)
Intra- or perinephric abscess Catheter-associated bacteriuria (normal hosts)
Urinary tract obstruction (total or relative [eg, benign prostatic
hypertrophy])
Catheter-associated bacteriuria (compromised hosts)
Prostate abscess
Pelvis Pelvic peritonitis Cervicitis
Tubo-ovarian abscess Vaginitis
Pelvic septic thrombophlebitis Pelvic inammatory disease
Lower respiratory tract CAP (normal host) Pharygnitis
CAP (asplenia/hyposplenism) Sinusitis
Empyema Mastoiditis
Lung abscess Bronchitis
Nosocomial pneumonia CAP (normal host)
3
2
0
C
U
N
H
A
Skin and soft tissue Complicated skin and skin-structure infections Osteomyelitis
Necrotizing fasciitis Uncomplicated skin and soft-tissue infections
Clostridial myonecrosis
Intravascular system Central intravenous lines Arterial lines
Peripherally inserted central catheter lines Peripheral intravenous lines
Hickman/Broviac catheters
Infected intravascular prosthetic devices
Arteriovenous grafts
Septic thrombophlebitis
Cardiovascular system Acute bacterial endocarditis Subacute bacterial endocarditis
Myocardial abscess
Paravalvular abscess
Other Toxic shock syndrome Relative adrenal insuciency
Dehydration
Data from Cunha BA. Sepsis and its mimics in the CCU. In: Cunha BA, editor. Infectious diseases in clinical practice. 2nd edition. New York: Informa
Healthcare; 2007.
3
2
1
S
E
P
S
I
S
&
S
E
P
T
I
C
S
H
O
C
K
per gram than any other organ system. The predominant organism in the
colonic ora is B fragilis. Making up the other component of the fecal ora
are aerobic GNBs, which are the organisms that cause bacteremia and peri-
tonitis. B fragilis is the predominant pathogen in lower intra-abdominal and
pelvic abscesses. When the integrity of the colon is breached and high num-
bers of GNBs are released into the peritoneum or bloodstream by infection
(eg, diverticulitis) or trauma (eg, surgery or colitis), sepsis is predictably fre-
quent. Therefore, for a patient to be considered septic, there should be
from the history, including the past medical history, physical examination,
and radiological examinations, indications of either a central intravenous
line infection or genitourinary or gastrointestinal source of infection. The
presence of gastrointestinal pathology not involving the colon or hepatobili-
ary tract makes sepsis unlikely. In the genitourinary tract, instrumentation
in sterile urine will not result in sepsis. Peripheral intravenous lines are
not associated with sepsis in contrast to central lines, which, if infected,
may cause sepsis [15,4446].
Clinical approach to sepsis and septic shock
Diagnostic approach
From the infectious disease perspective there are two major problems in
the empiric antimicrobial therapy of sepsis. First, before optimal therapy
can be selected, the presumptive diagnosis must be correct. In critical care
medicine, several medical conditions may mimic sepsis. The medical mimics
Box 1. Pseudosepsis: disorders that mimic sepsis
Common disorders
Diuretic-induced hypovolemia
Acute gastrointestinal hemorrhage
Acute pulmonary embolism
Acute myocardial infarction
Acute (edematous/necrotic) pancreatitis
Uncommon disorders
Diabetic ketoacidosis
SLE are
Relative adrenal insufciency
Rectus sheath hematoma
Data from Cunha BA. Sepsis and its mimics in the CCU. In: Cunha BA, editor.
Infectious diseases in clinical practice. 2nd edition. New York: Informa Healthcare;
2007.
322 CUNHA
of sepsis include those disorders that may present with fever, leukocytosis
with a left shift, and hypotension. Such patients may have Swan-Ganz cath-
eter readings that are compatible with sepsis in having a high peripheral
resistance and decreased cardiac output. The correct presumptive diagnosis
is essential for eective therapy in sepsis as well as in the disorders mimick-
ing sepsis. The medical mimics of sepsis include acute gastrointestinal
hemorrhage, acute pulmonary embolism/infarction, acute pancreatitis,
acute myocardial infarction, rectal sheath hematoma, and relative adrenal
insuciency.
Before concentrating on selecting an antibiotic for the empiric treatment
of sepsis, the clinician should consider and rule out the medical mimics of
sepsis, each of which requires very dierent therapy. If the medical mimics
of sepsis can be ruled out on the basis of history, physical examination, and
laboratory and radiologic tests, then the clinician should select a optimal
empiric agent for the monotherapy of sepsis based upon the location of
the infection, which determines the usual pathogens (Table 2) [3643].
Table 2
Clinical, laboratory, and hemodynamic parameters in sepsis and the disorders mimicking sepsis
Parameters Disorders mimicking sepsis
Sepsis bacteremia from
gastrointestinal, pelvic,
genitourinary, or intravenous
source
Microbiologic Negative blood cultures
(excluding skin contaminants)
Positive buy coat smear
Positive blood cultures
a
Hemodynamic [ peripheral vascular resistance [ peripheral vascular resistance
Y cardiac output Y cardiac output
Laboratory [ white blood cell count (with left
shift)
[ white blood cell count (with left
shift)
Normal platelet count Y platelet count
Y albumin Y albumin
[ brin split products [ brin split products
[ lactate [ lactate
[ D-dimers [ D-dimers
[ prothrombin time/partial
prothrombin time
[ prothrombin time/partial
prothrombin time
Y brinogen
Y a
2
globulins
Clinical Usually %102

F Usually R102

F
Hypotension Hypotension
Tachycardia Tachycardia
Respiratory alkalosis Respiratory alkalosis
a
May be negative if obtained late or if on antibiotic therapy.
Data fromCunha BA. Sepsis and its mimics in the CCU. In: Cunha BA, editor. Infectious dis-
eases in clinical practice. 2nd edition. New York: Informa Healthcare; 2007.
323 SEPSIS & SEPTIC SHOCK
Therapeutic approach
Eective empiric monotherapy should be started as soon as the medical
mimics of sepsis have been eectively ruled out and the presumptive diagno-
sis of sepsis has become the working diagnosis. The eects of antimicrobial
therapy are maximal when administered early in the infective process. The
most eective agent with an appropriate spectrum based on the site of the
infection and a high degree of activity against the presumed pathogen
should be selected for empiric monotherapy. The shotgun approach
with multiple drugs to be discontinued one by one subsequently indicates
that the prescriber does not understand the clinical pathologic concept
that site of infection clearly determines organisms. Although, local epidemi-
ologic resistance patterns need to be taken into account in selecting an ap-
propriate antimicrobial agent, because the spectrum of most agents remain
predictable over time. De-escalation therapy does not ensure that organisms
will not be missed. Rather, it duplicates coverage, which is often unneces-
sary, and may miss optimizing coverage against the most likely pathogens.
It is essential to get it right from the start and cover optimally the most likely
pathogens rather than all possible pathogens (Box 2) [4755].
Factors in empiric antibiotic therapy selection
Appropriate spectrum of activity
The selection of an empiric antibiotic for sepsis should take into account
spectrum, pharmacokinetics, resistance potential, safety prole, and cost.
Obviously, high degree of activity against the presumed pathogens (ie, spec-
trum) is the primary consideration, but side eect prole and resistance po-
tential are also important. If an antibiotic is used in high volume for the
empiric treatment of sepsis and is associated with frequent or severe side ef-
fects or high resistance potential, then the overall eect on patients in the
institution will ultimately be negative, although individual patients may
do well. Because of the primacy of spectrum, the antibiotic selected must
be based on the likely source of infection, which is the primary determinant
of the most likely pathogens to be encountered. Coverage should be directed
against the most common pathogens and does not need to be excessively
broad or contain unnecessary activity against uncommon pathogens. Anti-
biotics with the proper spectrum with similar side eects and resistant po-
tential will be equally eective in treating sepsis from various organs. If
these factors are equal, antibiotic selection may be based on dierences in
antibiotic costs [47,5355].
Prevention of antibiotic resistance
It is a popular misconception that overuse of antibiotics inevitably leads
to antibiotic resistance. The other common misconception is that over time
324 CUNHA
resistance to antibiotics is inevitable, leaving few eective antibiotics for
clinical use. Antibiotic resistance is associated with one or two antibiotics
in each antibiotic class. Antibiotic resistance is not only unrelated to class,
it is also unrelated to mechanism of antibiotic action or mechanism of
resistance. For example, except for ceftazidime, there is virtually no clini-
cally signicant antibiotic resistance among the other third-generation ceph-
alosporins, even after decades of high-volume use. Few other antibiotics
have been used as extensively as ceftriaxone and yet there is virtually no re-
sistance to this agent. Antibiotic resistance with a particular antibiotic is
Box 2. Clinical approach to the septic patient
Diagnosis
For both community and hospitalized patients presenting with
sepsis
Diagnose or rule out mimics of sepsis by history, physical
examination, and routine laboratory tests
Initiate medical therapy appropriate for disorders mimicking
sepsis
If mimics of sepsis are ruled out, determine site of septic focus in
critically ill patients presenting with sepsis, distinguish
colonization from infection in isolates from urine, respiratory
secretions, and noninfected wounds
Treat infection and avoid treating colonizing organisms
Interventions
Antibiotic interventions
Select empiric monotherapy based on coverage of predictable
pathogens determined by focus (organ) of infection
Select antibiotic with low resistance potential
Select antibiotic with a good safety prole
Non-antibiotic interventions
Administer aggressive and effective intravascular volume
replacement
If pressors are needed, give volume replacement before
pressors
Restore normothermia with heating blanket
Surgical intervention if sepsis is related to intra-abdominal
organ perforation or obstruction or abscess. For infected
devices, remove the device
Data from Cunha BA. Sepsis and its mimics in the CCU. In: Cunha BA, editor.
Infectious diseases in clinical practice. 2nd edition. New York: Informa Healthcare;
2007.
325 SEPSIS & SEPTIC SHOCK
usually related to one or two organisms. In the case of ceftazidime, resis-
tance is limited to P aeruginosa. Resistance to other aerobic GNBs is mini-
mal. Unfortunately, if ceftazidime is used to treat nonP aeruginosa aerobic
GNBs, resistance will develop to P aeruginosa [5660].
The other antibiotic resistance misconception that prolonged antibiotic
use inevitably leads to resistance, rendering the antibiotic ineectived has
been proven to be myth by the continued use of antibiotics (eg, doxycy-
cline) that have been used extensively for decades. Across all antibiotic
classes, similar analogies and examples substantiate the concept that anti-
biotic resistance is related to individual agents and not to classes, volume,
or duration of use. With the carbapenems, the same analogy applies. That
is, there is resistance to P aeruginosa with imipenem but not meropenem.
The resistance to imipenem, as with other high resistance potential an-
tibiotics appears early (ie, within 2 years postmarketing). Resistance either
occurs then or does not occur subsequently even after years of prolonged
use. Imipenem-resistant P aeruginosa was noted early and has continued.
When meropenem was introduced in 1996, there was some thought that
its lack of resistance was due to the newness of this carbapenem. There
was no resistance to P aeruginosa or other aerobic GNBs 2 years
postmeropenem release, which reliably predicted that there would be no
major resistance problems in the future with this antibiotic. Hence, mero-
penem is termed a low resistance potential antibiotic and its eectiveness
against P aeruginosa as well as against other aerobic GNBs continues to be
maintained.
Historical analysis, in the absence of a mechanistic explanation, pro-
vides the best way to describe the phenomenon of resistance involving dif-
ferent antibiotic classes. Neither structure activity relationships or
mechanism of resistance explains fully such dierences in resistance poten-
tial within each antibiotic class [5860]. Numerous examples may be given.
There are problems with tetracycline resistance to S pneumoniae and
S aureus, but doxycycline remains highly eective against S pneumoniae,
including penicillin-resistant strains, even after decades of use. Minocycline
is not only active MSSA, but is also a highly eective antibiotic against
MRSA, and its eectiveness has not diminished over time either. Among
the aminoglycosides, amikacin retains its eectiveness against aerobic
GNBs, including P aeruginosa, but resistance to gentamicin and tobramy-
cin remains a problem. For these reasons, amikacin may be termed a low
resistance potential antibiotic, whereas gentamicin and tobramycin can be
considered high resistance potential antibiotics. Excluding the clonal
spread of unusual or highly resistant GNBs, antibiotic-induced resistance
can be minimized by preferentially selecting low resistance potential an-
tibiotics in place of high resistance potential antibiotics for the treatment
of aerobic GNBs. Experience has validated this principle, which applies
to dierent antibiotic classes and to virtually all antibiotics in widespread
use [5658].
326 CUNHA
Control of antibiotic resistance
If an institution has a problem with a particular highly resistant
organism, infection control containment measures should prevent it from
spreading from patient to patient. In hospitals with a high prevalence of
multidrug-resistant GNBs, particular care should be taken with antibiotic
selection to not exacerbate an already dicult problem. Every attempt
should be made to avoid unnecessarily treating isolates that represent colo-
nization rather than infection. The most common errors made in this regard
relate to treating isolates from respiratory secretions in ventilated patients in
intensive care units. Treatment should be used when the clinical presentation
reects the pathologic expression (eg, clinical and chest x-ray features) of the
microbe isolated from respiratory secretions. Otherwise, isolates should be
considered colonizers until proven otherwise. The other common error in
mistaking and treating colonization for an infection occurs in patients
with indwelling Foley catheters. Catheter-associated bacteriuria nearly al-
ways represents colonization. While it is prudent to treat colonization of
the urinary tract in certain compromised hosts (eg, those with SLE, diabetes
mellitus, or multiple myeloma), there is no rationale for treating catheter-
associated bacteriuria in normal hosts. The reduction or elimination of
needless antimicrobial therapy directed against GNBs colonizing respiratory
secretions or urine would be an important step in reducing resistance in the
critical care setting. By avoiding treating of colonization and by using low
resistant potential antibiotics to treat bonied infections, antibiotic resis-
tance problems can be avoided, minimized, or eliminated [5659].
De-escalation therapy, intended to maximize initial coverage, is also in-
tended to decrease resistance by narrowing the spectrum of the eventual an-
tibiotic selected. However, there is no evidence that de-escalation therapy
actually decreases resistance. In treating CAP empirically with ceftriaxone,
there is no benet in changing therapy to penicillin if the organism is iden-
tied as S pneumoniae. The same analogy pertains to critical care medicine.
The key to optimal initial empiric therapy is in the careful selection of a sin-
gle agent that will cover the usually encountered pathogens [57,58].
For NPs and VAPs, optimal empiric monotherapy should be directed
against P aeruginosa. Antibiotics with a high degree of activity against P
aeruginosa will also be eective against other aerobic GNBs causing NP
and VAP. Adding anti-MRSA coverage is unnecessary because the inci-
dence of MRSA NP or VAP so low. In the rare event that an NP or
VAP patient should develop nosocomial MRSA pneumonia during hospi-
talization, then empiric anti-MRSA therapy may be added. If optimal anti-
pseudomonal monotherapy is selected using, for example, meropenem, then
an additional antipseudomonal agent (ie, cefepime, amikacin) need not be
added. An additional antipseudomonal drug is not needed since the antipseu-
domonal activity in meropenem is sucient for empiric antiP aeruginosa
coverage as well as monotherapy of P aeruginosa NP and VAP. If empiric
327 SEPSIS & SEPTIC SHOCK
therapy for NP or VAP consists of double antipseudomonal coverage plus
anti-MRSA coverage, the patient is subjected to two unnecessary antibiotics
[5760].
Monotherapy is always preferred to polypharmacy, which increases anti-
biotic costs, potential for antibiotic side eects, and potential for drugdrug
interactions. De-escalation therapy based on cultures from respiratory secre-
tions in ventilated patients is problematic, because of sampling error. Iso-
lates from respiratory secretions are not usually representative of lung
pathogens responsible for VAP. Because selective pressures in the respira-
tory ora brought about by antimicrobial therapy changes in the microbial
milieu of the intensive care unit, it is inaccurate to base antibiotic changes on
such isolates. The goal of empiric therapy should always be empiric mono-
therapy, thus avoiding the need to change or discontinue unnecessary anti-
biotics [58,60].
Antibiotic adverse eects
Patients who are septic already are critically ill and with varying degrees
of organ dysfunction. Antibiotic therapy is intended to halt and reverse the
septic process. Antibiotics used should not have serious side eects that
could add to the patients already precarious clinical state (eg, antibiotics as-
sociated with seizures [ie, imipenem, ciprooxacin, and metronidazole]). For
each of these drugs, there is an alternative not associated with seizures (eg,
meropenem, levooxacin, clindamycin) [60,61].
Critically ill patients being treated for sepsis are often complicated by an-
tibiotic-induced Clostridium dicile colitis. As with antibiotic resistance, the
antibiotic potential for causing C dicile diarrhea or colitis varies by anti-
biotic. Antibiotics that have little or no propensity or potential to cause
C dicile include carbapenems, linezolid, doxycycline, minocycline, tigecy-
cline, aminoglycosides, TMP-SMX, aztreonam, chloramphenicol, macro-
lides, vancomycin, colistin, and polymyxin B. The antibiotics most often
associated with C dicile are beta-lactam antibiotics, with the notable
exceptions of ceftriaxone, cefoperazone and piperacillin-tazobactam.
Quinolones vary in their potential for causing C dicile. There are also
good data to indicate that protein pump inhibitors predispose to C dicile
when combined with some antibiotics, particularly quinolones. Antibiotics
associated with severe hypersensitivity reactions and drug rashes, particu-
larly Steven-Johnson syndrome, should be avoided if possible and other
agents used instead (Table 3) [60,61].
Antibiotic therapy in the septic patient with penicillin allergy
Antimicrobial therapy in penicillin-allergic patients is problematic and is
particularly dicult in the critical care setting. Patients who are critically ill
are often unable to provide a history regarding allergic reactions to antimicro-
bials. Relatives and friends are often unfamiliar with or vague about details of
328 CUNHA
the patients hypersensitivity. Sometimes, but not always, medical records
help clarify the nature of the penicillin allergy. The physician should endeavor
to determine the nature of the penicillin allergy if at all possible. Particular
eort should be given to dierentiating anaphylactic from non-anaphylactic
reactions to penicillin. Nonanaphylactic reactions to penicillin include drug
fevers and drug rashes. Anaphlyactic reactions to penicillin include laryngo-
spasm, bronchospasm, hypotension, and generalized hives. Because hyper-
sensitivity reactions to antibiotics are stereotyped, ie, patients who have
laryngospasm upon penicillin rechallenge will manifest amaphylaxis again
as laryngospasm rather than as another hypersensitivity manifestation.
Patients who have a known history of nonanaphylactic penicillin reactions
may be given cephalosporins without concern. The cross-reactivity between
penicillins and cephalosporins is less than 5%. In the worst-case scenario, if
a patient with a nonanaphylactic penicillin allergy reacts to a cephalosporin,
the allergy would be manifested as either drug fever or drug rash and not as
an anaphylactoid reaction. Patients likely or are known to have had an ana-
phylactic reaction to penicillin should not be treated with penicillins or ceph-
alosporins. An antibiotic selected for such patients should have spectrum of
activity appropriate for the site of infection and should be from an antibiotic
class unrelated antigenically to penicillins or cephalosporins (eg, vancomycin,
linezolid, daptomycin, clindamycin, metronidazole, aminoglycosides, doxy-
cycline, quinolones, linezolid, azethreonam, tigecycline).
Table 3
Sepsis: antibiotic therapy based on infection source
Source or device Usual pathogens Usual nonpathogens
a
Emperic monotherapy
Lower gastrointestinal
tract, pelvis
b
B fragilis S aureus Meropenem
Aerobic GNBs E faecalis (VSE) Tigecycline
S aureus Ertapenem
Genitourinary tract,
kidney, prostate
b
Aerobic GNBs B fragilis Piperacillin-tazobactam
E faecalis (VSE) S aureus Meropenem
Central venous catheter
intravenous lines
S aureus B fragilis Meropenem
Aerobic GNBs Tigecycline
E faecalis Piperacillin/tazobactam
Pulmonary: NP, VAP P aeruginosa S aureus Meropenem
c
Aerobic GNBs Enterobacter sp Cefepime
B cepacia Cefoperazone
S maltophilia Levooxacin
E faecalis (VSE)
B fragilis
a
No need to include in empiric coverage.
b
Source unknown.
c
Vancomycin, daptomycin, or linezolid in most intravenous-line infections in institutions
where CVC infection due to MRSA more prevalent than CVC infection due to MSSA.
Data from Cunha BA, editor. Antibiotic essentials. 7th edition. Royal Oak (MI): Physicians
Press; 2008.
329 SEPSIS & SEPTIC SHOCK
Because of the structural similarities between beta-lactams and carbape-
nems, clinicians have been reluctant to use carbapenems in penicillin-allergic
patients. The cross-reactivity rates between carbapenems varies. Carbape-
nems are structurally related to beta-lactams. That is, they contain a beta-
lactam ring but are antigenically dissimilar. There is a very low but denite
cross-reactivity potential between imipenem-cilastatin in those allergic to
penicillins. However, there is little or no cross-reactivity potential with mer-
openem in treating penicillin-allergic patients. Hypersensitivity reactions
due to meropenem are extremely rare. Meropenem may be safely adminis-
tered, without penicillin skin testing. In the critical care setting, there is often
no time to perform penicillin allergy testing to patients giving a history of an
unknown penicillin allergy or with a denite history of anaphylaxis, and
without any allergic reactions. Because meropenem has become the corner-
stone of antibiotic monotherapy in critical care medicine in the treatment of
sepsis and septic shock, physicians should know that meropenem may be
given safely to such patients regardless of the type of previous penicillin-
hypersensitive reactions without the need of skin testing [6264].
Sepsis and septic shock: non-antibiotic therapies
Ventilatory and volume support are critical in patients with respiratory
insuciency or hypotension. Sepsis is an overly applied, imprecise diagnos-
tic term. It is all too frequently given to patients who become hypotensive
for any reason. Overzealous diuresis alone or dehydration can result in
hypotension with an increase in white blood cell count with a left shift ac-
companied by low-grade fevers. Thus diuresis, dehydration, and other non-
infectious disorders can result in pseudosepsis symptoms wrongly ascribed
to sepsis [37].
Septic shock is most frequently associated with lower abdominal pro-
cesses, such as a leak from or a rupture of an intra-abdominal abscess [35].
In such cases, the antibiotic treatment alone of septic shock will be ineec-
tive unless accompanied by early surgical intervention [44]. Patients with ur-
osepsis have the lowest mortality of patients with septic shock. Intravenous
linerelated sepsis has a high morbidity and mortality even if not compli-
cated by acute bacterial endocarditis [11,12,19].
Other adjunctive therapies have been used over the years in the treatment
of septic shock and include steroids and anticytokine agents. Antithrom-
botic drugs (eg, drotrecogin alpha) have serious side eects and no proven
benet. Since multiorgan dysfunction is, in part, endotoxin/cytokine medi-
ated, inhibition of endotoxin/cytokine release from GNB pathogens by
antibiotic therapy is important in septic shock. A few anti-GNB antibiotics
inhibit endotoxin/cytokine release, which is potentially benecial. Studies
vary in assessing the clinical eect of endotoxin inhibition or release depend
on the antibiotics used and how rapidly they were infused. Dierences in
330 CUNHA
endotoxin inhibition or release diers among studies. It appears that rapid
bolus antibiotic injection kills GNBs rapidly and minimizes the extent and
duration of endotoxin/cytokine eects, but slow and continuous infusion
prolongs endotoxin/cytokine release [6568]. Antibiotics that are often
used to treat sepsis and that are known to inhibit endotoxin/cytokine release
are meropenem, colistin, and polymyxin B. The cornerstone of septic shock
therapy remains early appropriate empiric therapy based on the site of infec-
tion as well as volume resuscitation, with or without pressors, and, if
needed, ventilatory support [43,55,60,6971].
Summary
Eective empiric antimicrobial therapy for sepsis depends upon selecting
an antibiotic which is highly active against a presumed pathogen which are
predictable and dependent upon the focus of the septic process. Unnecessarily
broad spectrum coverage for sepsis ignores basic infectious disease principles
based on location of infection and predictable pathogens determined by the
organ system involved. Unnecessarily broad or overlapping coverage with
multiple agents results in needless expense to the institution, the patient,
and the health care system. Polypharmacy increases potential drug side eects
as well as drugdrug interactions. It is almost always possible to empirically
treat sepsis with a single agent. Polypharmacy does not improve outcomes.
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