Sepsis and Septic Shock: Selectionof 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 inthe 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 fundamentalpathophysiological determinant of sepsis. In patients who have sepsis, bac-teremia should be assumed if not demonstrated by stained buffy coat smearsor blood cultures. Host defenses are designed to prevent sepsis and septicshock from occurring. For sepsis to occur, a large bacterial inoculummust breach host defenses. The most common conditions associated withsepsis 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 siteof infection to a particular organ, which determines the pathogenic florain 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 shouldhave 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 ofmedical 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 mimicsepsis. The common medical mimics of sepsis include acute pulmonary

Crit Care Clin 24 (2008) 313–334

* 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 gastrointestinalhemorrhage, 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 therapyfor 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 termfor fever associated with bacteremia with or without hypotension. Bacter-emia may not be present if blood cultures are obtained late in the septicprocess. 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 sepsiswas 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, priorantibiotic treatment), bacteremia is nonetheless the essential and funda-mental pathophysiological determinant of sepsis. Even if blood culturesare negative for one of the aforementioned reasons, every effort shouldbe to demonstrate bacteremia in patients being diagnosed with sepsis.In sepsis, bacteremia should be demonstrated by stained buffy coat smearsor 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 therapyshould be highly effective against the presumed pathogen or pathogensand should be administered as early as possible. For antimicrobial therapyto be effective, other supportive measures (eg, volume replacement) must beof the correct type and volume, and must be given early in the septic pro-cess before pressors are given. Otherwise, volume replacement given afterpressors is ineffective and will not result in restoring adequate intravascularvolume [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 andGNBs are from the gastrointestinal or genitourinary tracts [4,9].

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Sepsis sources: central venous catheters

For CVC sepsis, coverage should be directed against Staphylococcusaureus. If methicillin-sensitive S aureus (MSSA) strains predominate in aninstitution, anti–methicillin-resistant S aureus (anti-MRSA) is not necessaryafter catheter removal. In critically ill patients, the CVC can be safelyremoved and sent for CVC semiquantitative tip culture and a new CVCcan 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 CVCshould remain in place. Conversely, if the CVC tip results are positive (ie,R15 colonies), the new CVC should be removed and another CVC insertedat 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 breachesthe normal skin barrier to infection and bacteria may be directly introducedinto the bloodstream and if present in sufficient numbers will result in clin-ical sepsis. Since MSSA/MRSA or aerobic GNBs are common pathogens inCVC infections, empiric coverage should include anti-MSSA and shouldprovide and GNB activity for presumed CVC infection (eg, meropenem ifMSSAO MRSA in CVC in hospital) covers both MSSA aerobic GNBs.In hospitals where MRSA is more prevalent than MSSA as a cause ofCVC line infections, tigecycline provides empiric monotherapy againstboth MRSA and most aerobic GNBs. Regardless of the presumed patho-gens in CVC-related infections, the primary therapeutic intervention isCVC removal [14,16].

Sepsis sources: genitourinary tract

Urosepsis is sepsis originating from the urinary tract, where the organismcultured 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, abnormalurinary tract anatomy, foreign bodies (stents), renal or bladder stones, orgenitourinary instrumentation with infected urine. Uropathogens causingurosepsis originate from the gastrointestinal tract and expectedly are aerobicGNBs 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. Thecolon contains more bacteria than any other organ. The fecal flora is pre-dominantly (w75%) Bacteroides fragilis. Most of the remaining anaerobicfecal flora are common coliforms (w20%) and less common aerobicGNBs, excluding Pseudomonas aeruginosa. The remaining portion of fecalflora (w5%) is comprised of group D enterococci. Of this, about 95% are

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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. Coverageagainst 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 theportal blood supply is derived from the colon [3–5].

Clinicians should endeavor to localize the probable source of sepsis byhistory, physical examination, and routine laboratory tests to determine or-gan-appropriate empiric antibiotic therapy [8,9]. For community-acquiredurosepsis, empiric coverage should provide coverage against aerobicGNBs 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 tocontrol and eliminate the infection. For coverage of community-acquiredor 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-acquiredpneumonia (HAP) or NP is ventilator-associated pneumonia (VAP).From the infectious disease perspective, NP, HAP, and VAP are causedby the same pathogens, have the same clinical presentation, and requirethe same approach to empiric antimicrobial therapy. Occasionally, patientswith HAP, NP, or VAP may be complicated by septic shock. There arethree NP, HAP, and VAP pathogens that have the potential to cause sepsisand septic shock. These are K pneumoniae, S aureus, and P aeruginosa. Kpneumoniae, S aureus, and P aeruginosa NPs are each characterized byhigh spiking fevers, cyanosis, hypotension, and rapid cavitation on chestradiograph. Necrotizing cavitary pneumonias, S aureus (MSSA orMRSA), and P aeruginosa are characterized by rapid cavitation on radio-graph within 72 hours after clinical onset. The cavitation associated with Kpneumoniae typically occurs within 3 to 5 days after onset. Hemorrhagic

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cavitary pneumonia is a characteristic feature of MSSA and MRSA pneu-monias including influenza related MSSA/MRSA CAPs. The absence ofrapid cavitation and hemorrhagic necrotic pneumonia without high spikingfevers, cyanosis, or hypotension argues against the diagnosis of communityor nosocomial acquired staphylococcal pneumonia. Although a quarter toa third of ventilated patients in intensive care units have MSSA or MRSAcolonization of respiratory secretions, MSSA and MRSA NP remainsa distinctive and uncommon clinical entity. In the author’s experience,nosocomial staphylococcal pneumonias are very uncommon with nomore than one or two cases encountered per year.

CAPs are not associated with sepsis or septic shock except in threecircumstances. 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 ismore likely to present with sepsis and shock then its community-acquiredcounterpart. P aeruginosa is not a cause of CAP except in patients with cys-tic fibrosis or chronic bronchiectasis and even in these patients does notpresent with sepsis or septic shock. Patients who have febrile neutropeniawho 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 withsepsis 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 ofinfluenza, S aureus is rarely, if ever, a CAP pathogen. Viral influenzawith associated tracheo-bronchial damage predispose to necrotizing hem-orrhagic MSSA and MRSA CAP. Viral influenza alone is associatedwith 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 termsof 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 ordiminished splenic function. Such patients usually present with overwhelm-ing pneumococcal sepsis rather than pneumococcal pneumonia even if theinitial site of infection is the lungs or upper respiratory tract. Patientswho have overwhelming pneumococcal sepsis, unlike those who have otherpneumonias, present with a diffuse petechial or ecchymotic rash and shockat the outset so that the Roentgen manifestations of pneumonia usuallyhave no time to develop [23,27–31].

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Septic sources: skin and soft tissue

Uncomplicated skin and soft-tissue infections are rare causes of sepsisand 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 orS aureus. TSS is characterized by multiorgan dysfunction and may be fatal,but TSS is primarily a toxin-mediated disorder rather than a septic processper se. Necrotizing fasciitis may be accompanied by sepsis and septic shockif untreated. Necrotizing fasciitis may be complicated by TSS when due togroup 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 byCA-MRSA. CA-MRSA may be associated with a highly virulent gene, thePVL gene. CA-MRSA strains may be PVL positive or negative. Commu-nity-acquired PVL-negative strains resemble in their clinical presentationand severity MSSA, HA-MRSA, or CO-MRSA. However, CA-MRSAstrains 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 isprudent 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 onin 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 orcephalosporins by in vitro susceptibility testing, but these drugs are ineffec-tive in vivo. Therefore, when confronted with a patient with sepsis or septicshock due to MRSA, it is prudent to use one of the anti-MRSA drugs (ie,vancomycin, daptomycin, linezolid, or tigecycline) that have proven clinicalefficacy. A major clinical mistake is to assume that all MRSA infectionsadmitted from the community are CA-MRSA infections.

Virtually all patients presenting to hospitals from the community withMRSA have CO-MRSA rather than CA-MRSA. CA-MRSA, bothPVL-positive and PVL-negative, presents only as one of two clinicalsyndromesdas severe necrotizing pyodermas or as necrotizing CAP inpatients with influenza or influenzalike illnesses. Patients presenting fromthe community with MRSA without either of these clinical syndromesshould be assumed to have CO-MRSA and treated accordingly. Patientswith 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

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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 diseasewith clinical manifestations related to clostridial exotoxins. For this reason,there is little fever associated with gas gangrene and the treatment of gasgangrene (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. Complicatedskin and soft-tissue infections in compromised hosts, such as patients withdiabetes mellitus, may present with sepsis or septic shock (Table 1) [1–3,32].

Mimics of sepsis: medical mimics of the acute surgical abdomen

Several conditionsmay presentwith acute abdominal pain accompanied byfever, leukocytosis, and hypotension, mimicking intra-abdominal sepsis.These medical disorders include ‘‘diabetic crisis’’ in diabetic patients whohave ketoacidosis, a ‘‘luetic crisis’’ in patients who have syphilis, ‘‘right-rectussyndrome’’ in patients who haveEpstein-Barr virus infectiousmononucleosis,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 inruling out the other causes of pseudosepsis, clinicians should endeavor to ar-rive at the correct diagnosis because each disorder mimicking sepsis requiresa different therapeutic approach. If the diagnosis of the medical mimics of theacute abdomen is not clear at the time of presentation by history, physical ex-amination, or routine laboratory tests, then empiric antimicrobial therapy isunnecessary, but not unreasonable (Box 1) [36–43].

Sepsis: acute surgical abdomen

The upper gastrointestinal tract has relatively low numbers of aerobicGNBs, which is why perforation to the upper gastrointestinal tract doesnot ordinarily result in sepsis. The colon, in contrast, has more bacteria

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 inflammatory disease

Lower respiratory tract CAP (normal host) Pharygnitis

CAP (asplenia/hyposplenism) Sinusitis

Empyema Mastoiditis

Lung abscess Bronchitis

Nosocomial pneumonia CAP (normal host)

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CUNHA

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 insufficiency

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.

321

SEPSIS

&SEPTIC

SHOCK

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.

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per gram than any other organ system. The predominant organism in thecolonic flora is B fragilis. Making up the other component of the fecal floraare aerobic GNBs, which are the organisms that cause bacteremia and peri-tonitis. B fragilis is the predominant pathogen in lower intra-abdominal andpelvic 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 befrom 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. Thepresence of gastrointestinal pathology not involving the colon or hepatobili-ary tract makes sepsis unlikely. In the genitourinary tract, instrumentationin sterile urine will not result in sepsis. Peripheral intravenous lines arenot associated with sepsis in contrast to central lines, which, if infected,may cause sepsis [1–5,44–46].

Clinical approach to sepsis and septic shock

Diagnostic approach

From the infectious disease perspective there are two major problems inthe empiric antimicrobial therapy of sepsis. First, before optimal therapycan be selected, the presumptive diagnosis must be correct. In critical caremedicine, several medical conditions may mimic sepsis. The medical mimics

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of sepsis include those disorders that may present with fever, leukocytosiswith 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 diagnosisis essential for effective therapy in sepsis as well as in the disorders mimick-ing sepsis. The medical mimics of sepsis include acute gastrointestinalhemorrhage, acute pulmonary embolism/infarction, acute pancreatitis,acute myocardial infarction, rectal sheath hematoma, and relative adrenalinsufficiency.

Before concentrating on selecting an antibiotic for the empiric treatmentof sepsis, the clinician should consider and rule out the medical mimics ofsepsis, each of which requires very different therapy. If the medical mimicsof sepsis can be ruled out on the basis of history, physical examination, andlaboratory and radiologic tests, then the clinician should select a optimalempiric agent for the monotherapy of sepsis based upon the location ofthe 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 %102�F Usually R102�FHypotension 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.

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Therapeutic approach

Effective empiric monotherapy should be started as soon as the medicalmimics of sepsis have been effectively ruled out and the presumptive diagno-sis of sepsis has become the working diagnosis. The effects of antimicrobialtherapy are maximal when administered early in the infective process. Themost effective agent with an appropriate spectrum based on the site of theinfection and a high degree of activity against the presumed pathogenshould be selected for empiric monotherapy. The ‘‘shotgun approach’’with multiple drugs to be discontinued one by one subsequently indicatesthat the prescriber does not understand the clinical pathologic conceptthat 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 remainpredictable over time. De-escalation therapy does not ensure that organismswill 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 likelypathogens 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 accountspectrum, 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 theempiric 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 maydo well. Because of the primacy of spectrum, the antibiotic selected mustbe based on the likely source of infection, which is the primary determinantof the most likely pathogens to be encountered. Coverage should be directedagainst the most common pathogens and does not need to be excessivelybroad 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. Ifthese 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 leadsto antibiotic resistance. The other common misconception is that over time

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 testsInitiate medical therapy appropriate for disorders mimicking

sepsisIf mimics of sepsis are ruled out, determine site of septic focus in

critically ill patients presenting with ‘‘sepsis’’, distinguishcolonization from infection in isolates from urine, respiratorysecretions, and noninfected wounds

Treat infection and avoid treating colonizing organisms

InterventionsAntibiotic interventions

Select empiric monotherapy based on coverage of predictablepathogens determined by focus (organ) of infection

Select antibiotic with low resistance potentialSelect antibiotic with a good safety profile

Non-antibiotic interventionsAdminister aggressive and effective intravascular volume

replacementIf pressors are needed, give volume replacement before

pressorsRestore normothermia with heating blanketSurgical intervention if sepsis is related to intra-abdominal

organ perforation or obstruction or abscess. For infecteddevices, 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.

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resistance to antibiotics is inevitable, leaving few effective antibiotics forclinical use. Antibiotic resistance is associated with one or two antibioticsin each antibiotic class. Antibiotic resistance is not only unrelated to class,it is also unrelated to mechanism of antibiotic action or mechanism ofresistance. 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 antibioticshave been used as extensively as ceftriaxone and yet there is virtually no re-sistance to this agent. Antibiotic resistance with a particular antibiotic is

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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 antibioticuse inevitably leads to resistance, rendering the antibiotic ineffectived hasbeen proven to be myth by the continued use of antibiotics (eg, doxycy-cline) that have been used extensively for decades. Across all antibioticclasses, 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. Thatis, 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 eitheroccurs then or does not occur subsequently even after years of prolongeduse. Imipenem-resistant P aeruginosa was noted early and has continued.When meropenem was introduced in 1996, there was some thought thatits lack of resistance was due to the newness of this carbapenem. Therewas no resistance to P aeruginosa or other aerobic GNBs 2 yearspost–meropenem release, which reliably predicted that there would be nomajor resistance problems in the future with this antibiotic. Hence, mero-penem is termed a ‘‘low resistance potential’’ antibiotic and its effectivenessagainst P aeruginosa as well as against other aerobic GNBs continues to bemaintained.

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 ormechanism 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. Minocyclineis not only active MSSA, but is also a highly effective antibiotic againstMRSA, and its effectiveness has not diminished over time either. Amongthe aminoglycosides, amikacin retains its effectiveness against aerobicGNBs, including P aeruginosa, but resistance to gentamicin and tobramy-cin remains a problem. For these reasons, amikacin may be termed a ‘‘lowresistance potential’’ antibiotic, whereas gentamicin and tobramycin can beconsidered ‘‘high resistance potential’’ antibiotics. Excluding the clonalspread of unusual or highly resistant GNBs, antibiotic-induced resistancecan be minimized by preferentially selecting ‘‘low resistance potential’’ an-tibiotics in place of high resistance potential antibiotics for the treatmentof aerobic GNBs. Experience has validated this principle, which appliesto different antibiotic classes and to virtually all antibiotics in widespreaduse [56–58].

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Control of antibiotic resistance

If an institution has a problem with a particular highly resistantorganism, infection control containment measures should prevent it fromspreading from patient to patient. In hospitals with a high prevalence ofmultidrug-resistant GNBs, particular care should be taken with antibioticselection to not exacerbate an already difficult problem. Every attemptshould be made to avoid unnecessarily treating isolates that represent colo-nization rather than infection. The most common errors made in this regardrelate to treating isolates from respiratory secretions in ventilated patients inintensive care units. Treatment should be used when the clinical presentationreflects the pathologic expression (eg, clinical and chest x-ray features) of themicrobe isolated from respiratory secretions. Otherwise, isolates should beconsidered colonizers until proven otherwise. The other common error inmistaking and treating colonization for an infection occurs in patientswith indwelling Foley catheters. Catheter-associated bacteriuria nearly al-ways represents colonization. While it is prudent to treat colonization ofthe urinary tract in certain compromised hosts (eg, those with SLE, diabetesmellitus, or multiple myeloma), there is no rationale for treating catheter-associated bacteriuria in normal hosts. The reduction or elimination ofneedless antimicrobial therapy directed against GNBs colonizing respiratorysecretions or urine would be an important step in reducing resistance in thecritical care setting. By avoiding treating of colonization and by using ‘‘lowresistant 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 therapyactually 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 directedagainst P aeruginosa. Antibiotics with a high degree of activity against Paeruginosa will also be effective against other aerobic GNBs causing NPand 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 orVAP 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, thenan additional antipseudomonal agent (ie, cefepime, amikacin) need not beadded. An additional antipseudomonal drug is not needed since the antipseu-domonal activity in meropenem is sufficient for empiric anti–P aeruginosacoverage as well as monotherapy of P aeruginosa NP and VAP. If empiric

328 CUNHA

therapy for NP or VAP consists of double antipseudomonal coverage plusanti-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–druginteractions. 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 lungpathogens responsible for VAP. Because selective pressures in the respira-tory flora brought about by antimicrobial therapy changes in the microbialmilieu of the intensive care unit, it is inaccurate to base antibiotic changes onsuch 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 degreesof organ dysfunction. Antibiotic therapy is intended to halt and reverse theseptic process. Antibiotics used should not have serious side effects thatcould add to the patient’s already precarious clinical state (eg, antibiotics as-sociated with seizures [ie, imipenem, ciprofloxacin, and metronidazole]). Foreach 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, theantibiotic potential for causing C difficile diarrhea or colitis varies by anti-biotic. Antibiotics that have little or no propensity or potential to causeC 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 notableexceptions of ceftriaxone, cefoperazone and piperacillin-tazobactam.Quinolones vary in their potential for causing C difficile. There are alsogood data to indicate that protein pump inhibitors predispose to C difficilewhen combined with some antibiotics, particularly quinolones. Antibioticsassociated with severe hypersensitivity reactions and drug rashes, particu-larly Steven-Johnson syndrome, should be avoided if possible and otheragents used instead (Table 3) [60,61].

Antibiotic therapy in the septic patient with penicillin allergy

Antimicrobial therapy in penicillin-allergic patients is problematic and isparticularly difficult in the critical care setting. Patients who are critically illare often unable to provide a history regarding allergic reactions to antimicro-bials. Relatives and friends are often unfamiliar with or vague about details of

Table 3

Sepsis: antibiotic therapy based on infection source

Source or device Usual pathogens Usual nonpathogensa Emperic monotherapy

Lower 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.

329SEPSIS & SEPTIC SHOCK

the patient’s hypersensitivity. Sometimes, but not always, medical recordshelp clarify the nature of the penicillin allergy. The physician should endeavorto determine the nature of the penicillin allergy if at all possible. Particulareffort should be given to differentiating anaphylactic from non-anaphylacticreactions to penicillin. Nonanaphylactic reactions to penicillin include drugfevers 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 havelaryngospasm upon penicillin rechallenge will manifest amaphylaxis againas laryngospasm rather than as another hypersensitivity manifestation.

Patients who have a known history of nonanaphylactic penicillin reactionsmay be given cephalosporins without concern. The cross-reactivity betweenpenicillins and cephalosporins is less than 5%. In the worst-case scenario, ifa patient with a nonanaphylactic penicillin allergy reacts to a cephalosporin,the allergy would be manifested as either drug fever or drug rash and not asan 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 ofactivity appropriate for the site of infection and should be from an antibioticclass unrelated antigenically to penicillins or cephalosporins (eg, vancomycin,linezolid, daptomycin, clindamycin, metronidazole, aminoglycosides, doxy-cycline, quinolones, linezolid, azethreonam, tigecycline).

330 CUNHA

Because of the structural similarities between beta-lactams and carbape-nems, clinicians have been reluctant to use carbapenems in penicillin-allergicpatients. 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 definitecross-reactivity potential between imipenem-cilastatin in those allergic topenicillins. However, there is little or no cross-reactivity potential with mer-openem in treating penicillin-allergic patients. Hypersensitivity reactionsdue to meropenem are extremely rare. Meropenem may be safely adminis-tered, without penicillin skin testing. In the critical care setting, there is oftenno time to perform penicillin allergy testing to patients giving a history of anunknown 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 ofsepsis and septic shock, physicians should know that meropenem may begiven 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 respiratoryinsufficiency or hypotension. Sepsis is an overly applied, imprecise diagnos-tic term. It is all too frequently given to patients who become hypotensivefor any reason. Overzealous diuresis alone or dehydration can result inhypotension 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 ascribedto 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. Intravenousline–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 treatmentof 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 byantibiotic therapy is important in septic shock. A few anti-GNB antibioticsinhibit endotoxin/cytokine release, which is potentially beneficial. Studiesvary in assessing the clinical effect of endotoxin inhibition or release dependon the antibiotics used and how rapidly they were infused. Differences in

331SEPSIS & SEPTIC SHOCK

endotoxin inhibition or release differs among studies. It appears that rapidbolus antibiotic injection kills GNBs rapidly and minimizes the extent andduration of endotoxin/cytokine effects, but slow and continuous infusionprolongs endotoxin/cytokine release [65–68]. Antibiotics that are oftenused to treat sepsis and that are known to inhibit endotoxin/cytokine releaseare meropenem, colistin, and polymyxin B. The cornerstone of septic shocktherapy remains early appropriate empiric therapy based on the site of infec-tion as well as volume resuscitation, with or without pressors, and, ifneeded, ventilatory support [43,55,60,69–71].

Summary

Effective empiric antimicrobial therapy for sepsis depends upon selectingan antibiotic which is highly active against a presumed pathogen which arepredictable and dependent upon the focus of the septic process. Unnecessarilybroad spectrum coverage for sepsis ignores basic infectious disease principlesbased on location of infection and predictable pathogens determined by theorgan system involved. Unnecessarily broad or overlapping coverage withmultiple 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 empiricallytreat sepsis with a single agent. Polypharmacy does not improve outcomes.

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