Septic Shock Selection of Antimicrobials CCCNA

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Sepsis and Septic Shock: Selection

of Empiric Antimicrobial Therapy

Burke A. Cunha, MD, MACPa,b,*aInfectious Disease Division, Winthrop-University Hospital, Mineola,

NY 11501, USAbState 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 buffy 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 flora

in the septic process. The usual pathogens are determined by the organ orinfection 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 effects, 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

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infarction and embolism, acute myocardial infarction, acute gastrointestinal

hemorrhage, acute edematous or necrotic pancreatitis, overzealous antidiu-

retic therapy, and relative adrenal insufficiency in patients on chronic steroidtherapy. 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 different definitions 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 definition of sepsis

was broadened to include more patients for study purposes. However,

this definition 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 effort should

be to demonstrate bacteremia in patients being diagnosed with sepsis.In sepsis, bacteremia should be demonstrated by stained buffy coat smears

or blood cultures or assumed to be present [1–8].

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 effective against the presumed pathogen or pathogens

and should be administered as early as possible. For antimicrobial therapy

to be effective, 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 ineffective 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, anti–methicillin-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 different site [11–16].

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 sufficient 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]) [17–19].

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 flora is pre-

dominantly (w75%) Bacteroides fragilis. Most of the remaining anaerobic

fecal flora are common coliforms (w20%) and less common aerobic

GNBs, excluding Pseudomonas aeruginosa. The remaining portion of fecal

flora (w5%) is comprised of group D enterococci. Of this, about 95% are

315SEPSIS & 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),specific 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, levofloxacin, 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 [3–5].

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, anti– P aeruginosa coverage should be provided.

As with CVC line infections, if urosepsis is due to obstruction, stone, foreignbody (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, levofloxacin, 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 classified 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 influenza related MSSA/MRSA CAPs. The absence of

rapid cavitation and hemorrhagic necrotic pneumonia without high spikingfevers, 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 author’s 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 fibrosis 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 influenza or an influenzalike ill-

ness. Most staphylococcal pneumonias seen in the hospital are commu-

nity acquired and superimposed upon viral influenza. In the absence of

influenza, S aureus is rarely, if ever, a CAP pathogen. Viral influenza

with associated tracheo-bronchial damage predispose to necrotizing hem-

orrhagic MSSA and MRSA CAP. Viral influenza alone is associated

with a high mortality and morbidity even in young healthy adults. Cer-

tainly patients with viral influenza and superimposed MSSA or MRSApneumonia are critically ill. However, it is difficult 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

[21–26].

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 diffuse petechial or ecchymotic rash and shock

at the outset so that the Roentgen manifestations of pneumonia usually

have no time to develop [23,27–31].




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-I–producing 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 [32–35].

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 traumaat 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 effectiveness clinically.

Typically, some MRSA strains appear to be susceptible to quinolones or

cephalosporins by in vitro susceptibility testing, but these drugs are ineffec-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

efficacy. 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

syndromesd

as severe necrotizing pyodermas or as necrotizing CAP inpatients with influenza or influenzalike 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 influenza,

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) [1–3,32].

Mimics of sepsis: medical mimics of the acute surgical abdomenSeveral conditions may present with acute abdominal pain accompanied by

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) flare 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 specific 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 different 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) [36–43].

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




Table 1Clinical conditions associated with sepsis and nonseptic disorders

Source condition, disorder, or device

Source area Associated with sepsis Not a

Gastrointestinal tract Liver abscess Esoph

Gallbladder wall abscess Gastri

Cholangitis Pancre

Colon perforation Gastro

Colitis

Diverticulitis

Toxic megacolonAbscess

Genitourinary tract Renal or bladder calculi Urethr

Pyelonephritis Cystiti

Intra- or perinephric abscess Cathet

Urinary tract obstruction (total or relative [eg, benign prostatic

hypertrophy])

Catheter-associated bacteriuria (compromised hosts)

Prostate abscess

Pelvis Pelvic peritonitis Cervic

Tubo-ovarian abscess Vagini

Pelvic septic thrombophlebitis Pelvic

Lower respiratory tract CAP (normal host) Pharyg

CAP (asplenia/hyposplenism) Sinusi

Empyema Masto

Lung abscess Bronc

Nosocomial pneumonia CAP (



Skin and soft tissue Complicated skin and skin-structure infections Osteom

Necrotizing fasciitis Uncom

Clostridial myonecrosis

Intravascular system Central intravenous lines Arteri

Peripherally inserted central catheter lines Periph

Hickman/Broviac cathetersInfected intravascular prosthetic devices

Arteriovenous grafts

Septic thrombophlebitis

Cardiovascular system Acute bacterial endocarditis Subac

Myocardial abscess

Paravalvular abscess

Other Toxic shock syndrome Relativ

Dehyd

Data from Cunha BA. Sepsis and its mimics in the CCU. In: Cunha BA, editor. Infectious diseases in clinical pr

Healthcare; 2007.



per gram than any other organ system. The predominant organism in thecolonic flora is B fragilis. Making up the other component of the fecal flora

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 intravenousline 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 [1–5,44–46].

Clinical approach to sepsis and septic shockDiagnostic 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 flare Relative adrenal insufficiency

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 peripheralresistance and decreased cardiac output. The correct presumptive diagnosis

is essential for effective 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

insufficiency.

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 different therapy. If the medical mimicsof 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) [36–43].

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 buffy coat smear

Positive blood culturesa

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

[ fibrin split products [ fibrin split products

[ lactate [ lactate

[ D-dimers [ D-dimers

[ prothrombin time/partial

prothrombin time

[ prothrombin time/partial

prothrombin time

Y fibrinogen

Y a2

globulins

Clinical Usually %102F Usually R102F

Hypotension Hypotension

Tachycardia Tachycardia

Respiratory alkalosis Respiratory alkalosis

a May be negative if obtained late or if on antibiotic therapy.

Data from Cunha 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.




Therapeutic approach

Effective empiric monotherapy should be started as soon as the medical

mimics of sepsis have been effectively ruled out and the presumptive diagno-

sis of sepsis has become the working diagnosis. The effects of antimicrobial

therapy are maximal when administered early in the infective process. The

most effective 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) [47–55].

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 profile, and cost.

Obviously, high degree of activity against the presumed pathogens (ie, spec-

trum) is the primary consideration, but side effect profile 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 effect on patients in theinstitution 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 effects and resistant po-

tential will be equally effective in treating sepsis from various organs. If

these factors are equal, antibiotic selection may be based on differences inantibiotic costs [47,53–55].

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 effective 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 significant 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

DiagnosisFor 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, respiratorysecretions, 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 profile

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.




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 non– P aeruginosa aerobicGNBs, resistance will develop to P aeruginosa [56–60].

The other antibiotic resistance misconception that prolonged antibiotic

use inevitably leads to resistance, rendering the antibiotic ineffectived 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

post–meropenem 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 effectiveness

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 differences in resistance poten-

tial within each antibiotic class [58–60]. Numerous examples may be given.

There are problems with tetracycline resistance to S pneumoniae andS aureus, but doxycycline remains highly effective against S pneumoniae,

including penicillin-resistant strains, even after decades of use. Minocycline

is not only active MSSA, but is also a highly effective antibiotic against

MRSA, and its effectiveness has not diminished over time either. Among

the aminoglycosides, amikacin retains its effectiveness 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 clonalspread 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 different antibiotic classes and to virtually all antibiotics in widespread

use [56–58].

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 difficult 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

reflects 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 bonified infections, antibiotic resis-

tance problems can be avoided, minimized, or eliminated [56–59].

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 benefit in changing therapy to penicillin if the organism is iden-

tified 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 effective 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 sufficient for empiric anti– P aeruginosa

coverage as well as monotherapy of P aeruginosa NP and VAP. If empiric




therapy for NP or VAP consists of double antipseudomonal coverage plus

anti-MRSA coverage, the patient is subjected to two unnecessary antibiotics

[57–60].Monotherapy is always preferred to polypharmacy, which increases anti-

biotic costs, potential for antibiotic side effects, and potential for drug–drug

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 flora 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 effects

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 effects that

could add to the patient’s already precarious clinical state (eg, antibiotics as-

sociated with seizures [ie, imipenem, ciprofloxacin, and metronidazole]). For

each of these drugs, there is an alternative not associated with seizures (eg,

meropenem, levofloxacin, clindamycin) [60,61].

Critically ill patients being treated for sepsis are often complicated by an-

tibiotic-induced Clostridium difficile colitis. As with antibiotic resistance, the

antibiotic potential for causing C difficile diarrhea or colitis varies by anti-

biotic. Antibiotics that have little or no propensity or potential to cause

C difficile include carbapenems, linezolid, doxycycline, minocycline, tigecy-

cline, aminoglycosides, TMP-SMX, aztreonam, chloramphenicol, macro-

lides, vancomycin, colistin, and polymyxin B. The antibiotics most oftenassociated with C difficile are beta-lactam antibiotics, with the notable

exceptions of ceftriaxone, cefoperazone and piperacillin-tazobactam.

Quinolones vary in their potential for causing C difficile. There are also

good data to indicate that protein pump inhibitors predispose to C difficile

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 difficult 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 patient’s 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

effort should be given to differentiating 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 nonpathogensa

Emperic monotherapyLower gastrointestinal

tract, pelvisbB fragilis S aureus Meropenem

Aerobic GNBs E faecalis (VSE) Tigecycline

S aureus Ertapenem

Genitourinary tract,

kidney, prostatebAerobic 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 Meropenemc

Aerobic GNBs Enterobacter sp Cefepime

B cepacia Cefoperazone

S maltophilia Levofloxacin

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.




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 definite

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 definite history of anaphylaxis, andwithout 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 [62–64].

Sepsis and septic shock: non-antibiotic therapies

Ventilatory and volume support are critical in patients with respiratory

insufficiency 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 [3–5].

In such cases, the antibiotic treatment alone of septic shock will be ineffec-

tive unless accompanied by early surgical intervention [44]. Patients with ur-

osepsis have the lowest mortality of patients with septic shock. Intravenous

line–related 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 effects and no provenbenefit. 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 beneficial. Studies

vary in assessing the clinical effect of endotoxin inhibition or release depend

on the antibiotics used and how rapidly they were infused. Differences in

330 CUNHA



endotoxin inhibition or release differs among studies. It appears that rapid

bolus antibiotic injection kills GNBs rapidly and minimizes the extent and

duration of endotoxin/cytokine effects, but slow and continuous infusionprolongs endotoxin/cytokine release [65–68]. 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 [43,55,60,69–71].

Summary

Effective 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 effectsas well as drug–drug interactions. It is almost always possible to empirically

treat sepsis with a single agent. Polypharmacy does not improve outcomes.

References

[1] Sibbald WJ, Marshall J, Christou N, et al. ‘‘Sepsis’’dclarity of existing terminology or more

confusion? Crit Care Med 1991;19:996–8.

[2] Lazaron V, Barke RA. Gram-negative bacterial sepsis and the sepsis syndrome. Urol Clin

North Am 1999;26:687–99.[3] Murray MJ, Kumar M. Sepsis and septic shock. Postgrad Med 1991;90:199–202.

[4] Hardaway RM. A review of septic shock. Am Surg 2000;66:22–9.

[5] Annane D, Bellisant E, Cavaillon JR. Septic shock. Lancet 2005;365:63–78.

[6] Opal SM, Cohen J. Clinical gram-positive sepsis: Does it fundamentally differ from gram

negative bacterial sepsis. Crit Care Med 1999;27:1608–16.

[7] Levy B, Bollaert PE. Clinical manifestations and complications of septic shock. In:

Dhainaut JG, Thijs LG, Park G, editors. Septic shock. Philadelphia: WB Saunders;

2000. p. 339–52.

[8] Cruz K, Dellinger RP. Diagnosis and source of sepsis: the utility of clinical findings. In:

Vincent CL, Carlet J, Opal SM, editors. The sepsis test. Boston: Kluwer Academic Pub-

lishers; 2002. p. 11–28.[9] Alberti C, Brun-Buisson C. The source of sepsis. In: Vincent JL, Carlet J, Opal SM, editors.

The sepsis text. Boston: Kluwer Academic Publishers; 2002. p. 491–503.

[10] Marshall JC. Control of the source of sepsis. In: Vincent JL, Carlet J, Opal SM, editors. The

sepsis text. Boston: Kluwer Academic Publishers; 2002. p. 525–38.

[11] Gill MV, Cunha BA. IV line sepsis. In: Cunha BA, editor. Infectious diseases in critical care

medicine. New York: Marcel Dekker; 1998. p. 57–65.

[12] Cunha BA. Intravenous line infections. Crit Care Clin 1998;339–46.




[13] Sacks-Berg A, Strampfer MJ, Cunha BA. Intravenous line sepsis due to suppurative throm-

bophlebitis. Heart Lung 1987;16:318–20.

[14] Bouza E, Burillo A, Munoz P. Catheter-related infections: diagnosis and intravascular treat-

ment. Clin Microbiol Infect 2002;8:265–74.

[15] Cunha BA. S aureus bacteremia: clinical treatment guideline. Antibiotics for Clinicians 2006;

10:365–7.

[16] Cunha BA. Central intraveous line infections in the critical care unit. In: Cunha BA, editor.

Infectious disease in critical care medicine. New York: Informa Healthcare; 2007. p. 283–90.

[17] Cunha BA. Urosepsis. J Crit Illn 1997;12:616–25.

[18] Cunha BA. Urosepsisddiagnostic and therapeutic approach. Intern Med 1996;17:85–93.

[19] Cunha BA. Urosepsis in the CCU. In: Cunha BA, editor. Infectious diseases in critical care

medicine. 2nd edition. New York: Informa Healthcare; 2007.

[20] Sacks-Berg A, Calubiran OV, Cunha BA. Sepsis asociated with transhepatic cholangiogra-

phy. J Hosp Infect 1992;20:43–50.

[21] Cunha BA, editor. Pneumonia essentials. 2nd edition. Royal Oak (MI): Physicians Press; 2008.

[22] Cunha BA. Severe community-acquired pneumonia in the critical care unit. In: Cunha BA,

editor. Infectious disease in critical care medicine. New York: Informa Healthcare; 2007.

p. 157–68.

[23] Cunha BA. Ventilator associated pneumonia: Monotherapy is optimal if chosen wisely. Crit

Care Med 2006;10:e141–2.

[24] Bouza E, Burilla A, Torres MV. Nosocomial pneumonia in the critical care unit. In: Cunha

BA, editor. Infectious disease in critical care medicine. NewYork: Informa Healthcare; 2007.

p. 169–204.

[25] Cunha BA. Clinical manifestations and antimicrobial therapy of methicillin resistant Staph-

ylococcus aureus (MRSA). Clin Microbiol Infect 2005;11:33–42.[26] Magira EE, Zervakis D, Routsi C, et al. Community-acquired methicillin-resistant Staphy-

lococcus aureus carrying Panton-Valentine leukocidin genes: a lethal cause of pneumonia in

an adult immunocompetent patient. Scand J Infect Dis 2007;39:466–9.

[27] Gopal V, Bisno AL. Fulminant pneumococcal infections in ‘‘normal’’ asplenic hosts. Arch

Intern Med 1977;137:1526–30.

[28] Waghorn DJ. Overwhelming infection in asplenic patients: Current best practice preventive

measures are not being followed. J Clin Pathol 2001;54:214–8.

[29] Bridgen ML, Pattullo AL. Prevention and management of overwhelming postsplenectomy

infectiondan update. Crit Care Med 1999;27:836–42.

[30] Fernbach DJ, Burdine JA Jr. Sepsis and functional asplenia. N Engl J Med 1970;282:

691.[31] Bisno AL, Freeman JC. The syndrome of asplenia, pneumococcal sepsis, and disseminated

intravascular coagulation. Ann Intern Med 1970;72:389–93.

[32] DiNubile MJ, Lipsky BA. Complicated infections of skin and skin structures: when the

infections is more than skin deep. J Antimicrob Chemother 2004;53:37–50.

[33] Fontes RA Jr, Ogilvie CM, Miclau T. Necrotizing soft tissue infections. J Am Acad Orthop

Surg 2000;8:151–8.

[34] Owa T, Hayashi S, Miyoshi M, et al. Successful treatment of necrotizing fasciitis due to

group A streptococcus with impending toxic shock syndrome. Intern Med 2003;42:914–5.

[35] Stevens DL. Streptococcal toxic shock syndrome associated with necrotizing fasciitis. Annu

Rev Med 2000;51:271–88.

[36] Kaiser ML, Wilson SE. Intra-abdominal surgical infections and their mimics in the criticalcare unit. In: Cunha BA, editor. Infectious disease in critical care medicine. New York: In-

forma Healthcare; 2007. p. 291–304.

[37] Cunha BA. Sepsis and its mimics. Intern Med 1992;13:48–55.

[38] Wilson PG, Manji M, Neoptolemos JP. Acute pancreatitis as a model of sepsis. J Antimicrob

Chemother 1998;41:51–63.

332 CUNHA



[39] Gabbay DS, Cunha BA. Pseudosepsis secondary to bilateral adrenal hemorrhage. Heart

Lung 1998;27:348–51.

[40] Hamid N, Spadafora P, Khalife ME, et al. Pseudosepsis: rectus sheath hematoma mimicing

septic shock. Heart Lung 2006;35:434–7.

[41] Melby MJ, Bergman K, Ramos T, et al. Acute adrenal insufficiency mimicking septic shock:

a case report. Pharmacotherapy 1988;8:69–71.

[42] McCriskin JW, Baisden CE, Spaccevento LJ, et al. Pseudosepsis after myocardial infarction.

Am J Med 1987;83:577–80.

[43] Cunha BA. Sepsis and mimics in the CCU. In: Cunha BA, editor. Infectious diseases in crit-

ical care medicine. 2nd edition. New York: Informa Healthcare; 2007.

[44] Marshall JC. Intra-abdominal infections. Microbes Infect 2004;6:1015–25.

[45] Vincent JL. Management of sepsis in the critical ill patients: key aspects. Expert Opin Phar-

macother 2006;7:2037–45.

[46] Fry DE, editor. Surgical infections. Boston: Little, Brown and Company; 1995. p. 227–302.

[47] Ambrose PG, Owens RC, Quintiliani R, et al. Antibiotic use in the critical care unit. Crit

Care Clin 1998;8:283–308.

[48] Dellinger RP. Current therapy for sepsis. Infect Dis Clin North Am 1999;13:495–509.

[49] Grossi P, Gasperina DD. Antimicrobial treatment of sepsis. Surg Infect 2006;7:87–91.

[50] Finch RG. Empirical choice of antibiotic therapy in sepsis. J R Coll Physicians Lond 2004;

34:528–32.

[51] Bochud PY, Glauser MP, Calandra T, et al. Antibiotics in sepsis. Intensive Care Med 2001;

27:33–48.

[52] Carlet J. Antibiotic management of severe infections in critically ill patients. In: Dhainaut

JG, Thijs LG, Park G, editors. Septic shock. Philadelphia: WB Saunders; 2000. p. 445–60.

[53] Cunha BA. Antibiotic treatment of sepsis. Med Clin North Am 1995;79:551–8.[54] Cunha BA. Factors in antibiotic selection for hospital formularies (Part I). Hosp Formul

1998;33:558–72.

[55] Cunha BA. Antibiotic selection in the CCU. In: Cunha BA, editor. Infectious diseases in crit-

ical care medicine. 2nd edition. New York: Informa Healthcare; 2007.

[56] Cunha BA. Effective antibiotic resistance and control strategies. Lancet 2001;57:1307–8.

[57] Cunha BA. Antibiotic resistance: control strategies. Crit Care Clin 1998;8:309–28.

[58] Cunha BA. Antibiotic selection and control of resistance in the critical care unit. In: Cunha

BA, editor. Infectious disease in critical care medicine. New York: Informa Healthcare; 2007.

p. 609–24.

[59] Cunha BA. Newer uses for older antibiotics: nitrofurantoin, amikacin, colistin, polymyxin b,

doxycycline and minocycline revisited. Med Clin North Am 2006;90:1089–107.[60] Cunha BA, editor. Antibiotic essentials. 7th edition. Royal Oak (MI): Physicians Press; 2008.

[61] Granowitz EV, Brown RB. Adverse reactions to antibiotics. In: Cunha BA, editor. Infec-

tious disease in critical care medicine. New York: Informa Healthcare; 2007. p. 575–94.

[62] Cunha BA. Clinical approach to antibiotic therapy in the penicillin allergic patient. Med Clin

North Am 2006;90:1257–64.

[63] Cunha BA. Antimicrobial therapy in the penicillin-allergic patient in the critical care unit. In:

Cunha BA, editor. Infectious disease in critical care medicine. New York: Informa Health-

care; 2007. p. 625–30.

[64] Cunha BA: Meropenem: lack of cross reactivity in penicillin allergic patients. J Chemother

2008, in press.

[65] Cunha BA, Wu P, Qadri SMH. Meropenem inhibition of endotoxin release from E coli .Advances of Therapy 1997;14:168–71.

[66] Danner RL, Elin RJ, Hossein JM, et al. Endotoxemia in human septic shock. Chest 1991;99:

169–75.

[67] Lepper PM, Tk Held, Schneider EM, et al. Clinical implications of antibiotic-induced endo-

toxin release in septic shock. Intensive Care Med 2002;28:824–33.




[68] Giamarellos-Bourboulis EJ, Mega A, Pavleas I, et al. Impact of carbapenem on systemic

endotoxemia in patients with severe sepsis and gram-negative bacteremia. J Chemother

2006;18:502–6.

[69] Court O, Kumar A, Parrillo JE, et al. Clinical review: myocardial depression in sepsis and

septic shock. Crit Care 2002;6:500–8.

[70] Vincent JL. International sepsis forum hemodynamic support in septic shock. Intensive Care

Med 2001;27:80–92.

[71] Callister ME, Evans TW. Haemodynamic and ventilatory support in severe sepsis. J R Coll

Physicians Lond 2000;34:522–8.

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