hai proceedings of hai summit clin infect dis.-2008-kollef-s55-99

HAI Summit Critical Appraisal • CID 2008:47 (Suppl 2) • S55

S U P P L E M E N T A R T I C L E

Health Care–Associated Infection (HAI): A CriticalAppraisal of the Emerging Threat—Proceedings ofthe HAI Summit

Marin H. Kollef,1,2 Lena M. Napolitano,3 Joseph S. Solomkin,4 Richard G. Wunderink,5 In-Gyu Bae,7

Vance G. Fowler,7 Robert A. Balk,6 Dennis L. Stevens,8 James J. Rahal,9,10 Andrew F. Shorr,11,12 Peter K. Linden,13

and Scott T. Micek1,2

1Washington University School of Medicine and 2Barnes-Jewish Hospital, St. Louis, Missouri; 3University of Michigan Health Center, Ann Arbor;4University of Cincinnati College of Medicine, Cincinnati, Ohio; 5Feinberg School of Medicine, Northwestern University, and 6Rush UniversityMedical Center and Rush Medical College, Chicago, Illinois; 7Duke University Medical Center, Durham, North Carolina; 8Veterans Affairs MedicalCenter, Boise, Idaho; 9New York Hospital Queens, Flushing, and 10Weill Medical College of Cornell University, New York, New York; 11WashingtonHospital Center and 12Georgetown University, Washington, DC; and 13University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

During the Health Care–Associated Pneumonia Summit conducted in June 2007, it was found that there is a

need for educational efforts in several areas of health care–associated infections (HAI) that extend beyond

pneumonia. This supplement to Clinical Infectious Diseases represents the proceedings of the HAI Summit,

a diverse panel of clinical investigators whose goal was to assess the quality of evidence regarding issues

surrounding HAI and to discuss potential implications for its diagnosis and treatment in the future.

The classification of bacterial infections is in a state of

flux. Most of the prior classification schemes have seg-

regated these infections according to the site of infec-

tion (e.g., lung, urinary tract, soft tissue and skin, and

intra-abdominal) and the location of the patient at the

time the infection developed. The latter has historically

been divided into community-acquired and nosocomial

(hospital-acquired) infections [1, 2]. Unfortunately,

this simple classification scheme is no longer adequate,

because of changing patient demographics and risk

profiles for infection with potentially antibiotic-resis-

tant bacteria, which historically have been encountered

primarily in the hospital setting.

Patients with serious infections (e.g., pneumonia,

bacteremia, and septic shock) should be given treat-

ment initially with antibiotics active against the bac-

terial pathogens causing the infection (i.e., appropriate

antibiotic therapy). Additionally, appropriate antibiotic

Reprints or correspondence: Dr. Marin H. Kollef, Div. of Pulmonary and CriticalCare Medicine, Washington University School of Medicine, 660 S. Euclid Ave.,Campus Box 8052, St. Louis, MO 63110 ([email protected]).

Clinical Infectious Diseases 2008; 47:S55–99� 2008 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2008/4707S2-0002$15.00DOI: 10.1086/590937

therapy should be administered in a timely manner to

optimize the likelihood of a clinical response. The sup-

port for these recommendations comes from investi-

gations demonstrating that patients initially given treat-

ment with antibiotic regimens that are not active against

the causative bacterial species (i.e., inappropriate an-

tibiotic therapy) have a greater risk for in-hospital mor-

tality than do patients receiving appropriate therapy [3–

5]. Classification schemes should assist clinicians in

identifying patients at risk for antibiotic-resistant in-

fections, thereby requiring initial treatment with broad-

spectrum antimicrobials. The recognition of potentially

antibiotic-resistant infections occurring outside the

hospital setting has resulted in the formulation of the

new category, termed “health care–associated infec-

tions” (HAIs). Implicit in the definition of HAIs is that

patients will require initial therapy with more broad-

spectrum antibiotics, compared with patients with

community-acquired infections.

HAIs have been defined using various criteria (table

1). Friedman et al. [6] evaluated patients admitted to

the hospital with bloodstream infections (BSIs) and

showed that individuals with HAI risk factors were sta-

tistically more likely than were patients with commu-

nity-acquired infections to be infected with anti-

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S56 • CID 2008:47 (Suppl 2) • Kollef et al.

Table 1. Risk factors used to define health care–associatedinfections.

Infection type [source] and criteria

Bacteremia [6]Health care–associated BSI was defined by a positive culture re-

sult for a blood specimen obtained from a patient at thetime of hospital admission or within 48 h after admissionif the patient fulfilled any of the following criteria:

1. Received intravenous therapy at home; received woundcare or specialized nursing care through a health careagency, family, or friends; or had self-administered intrave-nous medical therapy in the 30 days before the BSI. Pa-tients whose only home therapy was oxygen use wereexcluded.

2. Attended a hospital or hemodialysis clinic or received intra-venous chemotherapy in the 30 days before the BSI

3. Was hospitalized in an acute care hospital for �2 days inthe 90 days before the BSI

4. Resided in a nursing home or long-term-care facilityPneumonia [7]

HCAP was defined as a diagnosis of pneumonia in patients witha first positive bacterial respiratory culture finding within2 days of admission and any of the following:

1. Admission source indicates a transfer from another healthcare facility

2. Receiving long-term hemodialysis3. Prior hospitalization within 30 days for those whose condi-

tion does not meet VAP definitionPneumonia [8]

HCAP was defined as a diagnosis of pneumonia in patients ad-mitted to the hospital who met at least 1 of the followingcriteria:

1. Admission from a nursing home, rehabilitation hospital, orother long-term–nursing care facility

2. Previous hospitalization within the immediately preceding12 months

3. Receiving outpatient hemodialysis, peritoneal dialysis, or in-fusion therapy necessitating regular visits to a hospital-based clinic

4. Having an immunocompromised state

NOTE. Adapted from [6], from [7], and from [8]. BSI, bloodstream infection;HCAP, health care–associated pneumonia; VAP, ventilator-associated pneu-monia.

biotic-resistant bacteria, including methicillin-resistant Staphy-

lococcus aureus (MRSA) and antibiotic-resistant enterococci. In

an accompanying overview, the importance of the classification

of HAIs was emphasized in terms of identifying a group of

patients who would potentially benefit from initial treatment with

broad-spectrum antibiotics [9]. Similarly, Kollef et al. [7] ex-

amined 4543 patients with microbiologically confirmed pneu-

monia from a multicenter administrative database. They sepa-

rated patients into 4 categories: community-acquired pneumonia

(CAP), health care–associated pneumonia (HCAP), hospital-ac-

quired pneumonia (HAP), and ventilator-associated pneumonia

(VAP). Patients with HCAP had underlying comorbidities and

bacterial pathogens similar to those of patients with HAP and

VAP. The most common bacterial pathogen isolated in patients

with HCAP was MRSA. The in-hospital mortality rate among

patients with HCAP was similar to that observed among patients

with HAP (19.8% vs. 18.1%; ), both being almost twiceP � .005

the mortality rate observed among patients with CAP (10%;

for both comparisons) [7].P ! .001

The American Thoracic Society (ATS) and Infectious Diseases

Society of America (IDSA) guidelines for HCAP, HAP, and VAP

have summarized potential risk factors for HAIs (table 1) [1, 2].

These are the first published guidelines to recognize the category

of HCAP in terms of recommending initial broad-spectrum an-

timicrobial treatment because of the high prevalence of antibi-

otic-resistant bacteria as the causative agents of infection. Further

support for this recommendation comes from a large single-

center study evaluating patients with microbiologically confirmed

pneumonia admitted to an urban teaching hospital [8]. Among

the 639 patients with microbiologically confirmed pneumonia

evaluated in that study, HCAP made up 67.4% of the pneumonia

cases, and CAP accounted for 32.6%. Patients with HCAP were

statistically more likely to be infected with MRSA, Pseudomonas

aeruginosa, and other nonfermenting gram-negative rods, com-

pared with patients with CAP. Patients with HCAP were also

significantly more likely to have received inappropriate initial

antimicrobial therapy (28.3% vs. 13.0%; ) and hadP ! .001

greater in-hospital mortality (24.6% vs. 9.1%; ), com-P ! .001

pared with patients with CAP.

The importance of correctly classifying patients with HAI risk

profiles is demonstrated by 2 recent studies. Schramm et al. [5]

evaluated patients with MRSA sterile-site infections and showed

that patients with a positive sterile-site culture specimen obtained

during the first 48 h of hospitalization were significantly less

likely to have received empirical treatment for MRSA. This oc-

curred despite the fact that most patients had readily identifiable

risk factors for HAI, which suggests that the treating clinicians

did not recognize either the presence of these risk factors or the

associated therapeutic implications. In a prospective before-after

study using a protocol and standardized order set for the man-

agement of septic shock in the emergency department, a statis-

tically significant reduction (from 48.3% to 30%; ) inP p .04

28-day mortality was associated with the prescription of broad-

spectrum antibiotics to patients with risk factors for HAI [10].

These studies suggest that many patients evaluated during the

early periods of their hospitalization may benefit from having

their infection identified as an HAI, so that more-appropriate

initial antibiotic therapy can be prescribed.

During the HCAP Summit conducted in June 2007, it was

found that there is a need for educational efforts in several

areas of HAI that extend beyond pneumonia. This supplement

to Clinical Infectious Diseases represents the proceedings of a

diverse panel of clinical investigators whose goal was to assess

the quality of evidence in support of the clinical classification



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Table 2. Health Care–Associated Infection (HAI) Summit clini-cal practice statements.

Workshop 1: Treatment by Sites of Infection (statements 1–5)1. Patients at risk for health care–associated complicated skin

and soft tissue infections are more likely to have both resis-tant gram-negative and gram-positive pathogens. (L.M.N.)

2. Patients with health care–associated intra-abdominal infec-tions should receive dual empiric therapy for resistant gram-negative and gram-positive pathogens. (J.S.S.)

3. Early aggressive, appropriate empiric treatment and de-esca-lation for HCAP reduces mortality and minimizes resistance.(R.G.W.)

4. Health care–associated BSIs require empiric coverage forMDR gram-negative bacteria and MRSA, as well as coveragefor fungal pathogens in patients with specific risk factors.(V.G.F.)

5. Initial appropriate antimicrobial therapy and source control arethe most important determinants of outcome in severe sepsisand septic shock. (R.A.B.)

Workshop 2: Treatment by Organism (statements 6–10)6. Vancomycin is obsolete for treating MRSA infections. (D.L.S.)7. Serious HAIs due to suspected gram-negative bacteria should

be treated empirically with dual coverage that includes anaminoglycoside. (J.J.R.)

8. Patients with serious HAIs who have risk factors for fungalinfections require early empiric antifungal therapy to reducemortality. (A.F.S.)

9. All infections in immunocompromised patients should be con-sidered HAIs until proven otherwise. (P.K.L.)

10. Adjunctive therapy should be utilized to prevent and treatserious HAIs. (S.T.M.)

NOTE. BSI, bloodstream infection; HCAP, health care–associated pneu-monia; MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcusaureus.

Table 3. Workshop and Health Care–Associated Infection Sum-mit panel voting schemes.

Category Nature of evidence

I Evidence obtained from at least 1 well-designed,randomized, controlled trial

II Evidence obtained from well-designed cohort orcase-control studies

III Evidence obtained from case series, case reports,or flawed clinical trials

IV Opinions of respected authorities based on clini-cal experience, descriptive studies, or reportsof expert committees

V Insufficient evidence to form an opinion

Level of workshop support for statement

A There is good evidence to support the statementB There is fair evidence to support the statementC There is poor evidence to support the statement,

but recommendations may be made on othergrounds

D There is fair evidence to reject the statementE There is good evidence to reject the statement

Individual level of support

1 Accept recommendation completely2 Accept recommendation with some reservations3 Accept recommendation with major reservations4 Reject recommendation with reservations5 Reject recommendation completely

of HAI as a distinct entity and the need for specific therapeutic

interventions for HAI. Ten clinical practice statements were

drafted by the chair (M.H.K.) and the 2 workshop leaders

(L.M.N. and D.L.S.) and were subsequently evaluated by an

11-member panel with expertise in infectious diseases, surgery,

critical care, pharmacology, and outcomes research (table 2).

Before the summit was convened, each participant was assigned

a statement and was instructed to systematically review and

summarize the evidence supporting or refuting that statement.

In the first phase of the live meeting, the simultaneously

conducted workshops “Treatment by Sites of Infection” and

“Treatment by Organism” included a leader and 4 or 5 content

experts and served as a forum for each individual to present

the evidence for his or her assigned statement. When the data

were presented, primary attention was given to the study meth-

odology, the number of patients enrolled, and the outcome

events. After the presentation of data for each statement, work-

shop members discussed the evidence, graded the strength of

the evidence, and assigned the statement a consensus numeric

grade through a voting process (table 3).

In the second phase of the live meeting, all summit panelists

reconvened as a single group, reviewed the workshop sum-

maries, and discussed each statement further. After each dis-

cussion, all participants voted on their individual levels of sup-

port, using the grading scheme shown in table 3. In addition

to defining the level of evidence available for each statement,

the panel members also outlined additional data required to

further refine the statements for future clinical uses.

Before the summit meeting, clinical perspectives of prac-

ticing physicians were measured via a Web-based survey. E-

mail polling was done to ascertain their level of support for

the same 10 statements. The e-mail invitation to participate

in the electronic survey was sent to 3300 members of the

IDSA (all active e-mail addresses). Of the IDSA members

surveyed, 744 (23%) responded. The purpose of the electronic

surveys was to provide information that would allow for the

comparison of data-driven responses from the content “ex-

perts” at the summit with those from clinicians practicing in

the field. The summit participants and the surveyed physicians

used the same voting scheme for “Individual Level of Sup-

port” to grade the 10 statements (table 3).

This exercise was performed to determine the prevailing cur-

rent opinions regarding HAIs and areas where additional re-

search and knowledge is required. In this era of increasing

antimicrobial resistance, clinical decision making regarding the



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management of suspected bacterial infections has become in-

creasingly complex. Given factors such as the aging of our

population, the increasing use of immunomodulating therapies,

and the practice of caring for patients with more-complicated

cases outside of the hospital setting, it is very likely that the

prevalence of HAIs will increase. Research to better define this

category of infection and its management appears to be very

relevant.

STATEMENT 1: PATIENTS AT RISK FOR HEALTHCARE–ASSOCIATED COMPLICATED SKIN ANDSOFT-TISSUE INFECTIONS ARE MORE LIKELYTO HAVE BOTH RESISTANT GRAM-NEGATIVEAND GRAM-POSITIVE PATHOGENS

Rationale and Definition of Statement

Presently, there is no standard definition for health care–as-

sociated complicated skin and soft-tissue infection (cSSTI). The

terminology of HAIs was first devised as a new classification

scheme for BSIs to distinguish patients with community-ac-

quired, health care–associated, and nosocomial infections [6].

Skin and soft-tissue infections (SSTIs) have traditionally been

categorized as either uncomplicated or complicated infections,

by use of the US Food and Drug Administration (FDA) criteria

[11]. Uncomplicated skin infections include simple abscesses,

impetiginous lesions, furuncles, and cellulitis. Complicated skin

infections include deeper soft-tissue infections or those re-

quiring significant surgical intervention, such as infected ulcers,

burns, and major abscesses or a significant underlying disease

state that complicates the response to treatment. Superficial

infections or abscesses in an anatomical site, such as the rectal

area, where the risk of anaerobic or gram-negative pathogen

involvement is higher, should be considered complicated

infections.

The microbiology of uncomplicated and complicated skin

infections is not the same. In uncomplicated skin infections,

S. aureus and Streptococcus pyogenes are the 2 most commonly

seen pathogens. Among complicated skin infections, the pos-

sible pathogens are numerous, may be monomicrobial or po-

lymicrobial, and are dependent on the clinical situation, the

location of the infection, and the medical history of the indi-

vidual patient.

Because no standard definition for health care–associated

cSSTI is available, we will review data regarding HAIs in general

and the changing epidemiology of cSSTIs. This section aims to

assess the strength of evidence supporting the assertion that

patients at risk for health care–associated cSSTI are more likely

to be infected with both resistant gram-negative and gram-

positive pathogens.

Methods

A PubMed database search to identify studies related to the

clinical and microbiological features of health care–associated

cSSTIs was completed on 4 September 2007. The search term

“skin infections” yielded a total of 78,866 articles. The search

term “complicated skin and skin structure infection (cSSSI)”

yielded 244 articles, and the search term “complicated skin and

soft tissue infection (cSSTI)” yielded 100 articles. The search

terms “health care associated,” “healthcare associated,” and

“healthcare-associated” yielded 51,504, 38,460, and 288 articles,

respectively. Combining the search terms “health care associ-

ated,” “healthcare associated,” and “healthcare-associated” with

“infection,” using the “AND” function, produced 5154, 3759,

and 250 articles, respectively. Combining the search terms

“health care associated,” “healthcare associated,” and “health-

care-associated” with “skin infections,” using the “AND” func-

tion, produced 138, 109, and 5 articles, respectively. After lim-

iting these articles to the English language, a total of 147 articles

were reviewed, and 2 articles were deemed relevant to the

statement.

Evidence

Prevalence of health care–associated cSSTI. No studies were

identified as specifically focusing on the prevalence of health

care–associated cSSTI. One study specifically addressed the is-

sue of overall prevalence of HAIs in general and included a

cohort of patients with skin infections. This study involved a

cross-sectional population survey of patients, aged �19 years,

admitted to 25 acute-care hospitals participating in the Ca-

nadian Nosocomial Infection Surveillance Program, to deter-

mine the prevalence of HAIs. A 1-day HAI point-prevalence

survey was conducted in February 2002. Adult patients who

had been admitted at least 48 h before the day of the survey

were identified, and the primary outcome was the presence of

an HAI, which was identified as an infection not present at

admission and with onset at least 72 h after admission. Some

would consider these nosocomial infections. The study was

limited to the following infections: pneumonia, urinary-tract

infection, BSI, surgical-site infection, and Clostridium difficile

infection. Centers for Disease Control and Prevention (CDC)

definitions were used for all HAIs. A total of 5750 adults were

surveyed, 2086 (36%) of whom were receiving at least 1 sys-

temic antimicrobial agent; 601 patients had 667 HAIs, giving

a prevalence of 10.5% for infection and 11.6% for HAI. The

only skin infection reported was surgical-site infection, which

was identified in 146 patients (2.5%). In the multivariate logistic

regression model for HAI, the following characteristics were all

independently associated with HAI: extended hospital stays of

17 days before the day of the survey, having a central venous



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catheter, having an indwelling urinary catheter, or having an

endotracheal tube with or without mechanical ventilation [12].

Epidemiology and microbiology of health care–associated

cSSTI. No studies were identified that specifically focused on

the microbiology of health care–associated cSSTI. However,

multiple studies reported the microbiology of SSTIs in hos-

pitalized patients and patients presenting to the emergency

department.

The SENTRY Antimicrobial Surveillance Program, estab-

lished in 1997 by the Jones Group/JMI laboratories and funded

by SmithKline Beecham, is designed to monitor antimicrobial

resistance among various pathogens around the globe [13]. The

SENTRY program recently reported data regarding causative

isolates from SSTIs from 3 continents during a 7-year period

(1998–2004) [14]. Each year, participating medical centers sent

50 consecutive pathogens from hospitalized patients that were

determined to be significant causes of pyogenic wound infec-

tions. The isolates were from an SSTI or surgical-site infection

and were either community acquired or nosocomial in origin.

The predominant pathogens included S. aureus (ranked first

in all geographic regions), P. aeruginosa, Escherichia coli, and

Enterococcus species. On the global scale, S. aureus was the most

frequently occurring pathogen from an SSTI, with MRSA being

the greatest resistance concern. Considerable variation in the

MRSA rate was noted between countries and continents, with

the overall rate highest in North America (35.9%), followed by

Latin America (29.4%) and Europe (22.8%). It was noted that

the rate of MRSA in North America increased from 26.2% of

isolates in 1998 to 47.4% of isolates in 2004. Gram-negative

isolates as causes of SSTIs were common, and, among non-

Enterobacteriaceae gram-negative bacilli, P. aeruginosa had the

highest occurrence in SSTIs in all geographic regions.

Community-associated MRSA has increased markedly to be-

come the greatest problem facing treatment of SSTIs in the

outpatient setting. A comparison of community-associated and

health care–associated MRSA infections was performed as a

prospective cohort study of patients with MRSA infection iden-

tified at 12 Minnesota laboratory facilities from 1 January

through 31 December 2000. Of 1100 MRSA infections, 131

(12%) were community associated, and 937 (85%) were health

care associated. SSTIs were more common among community-

associated cases (75%) than among health care–associated cases

(37%) (OR, 4.25; 95% CI, 2.97–5.90) [15].

A prospective, observational study examined patients with

SSTIs presenting to the emergency department in an urban public

hospital in Oakland, California. Among the 137 patients enrolled,

MRSA was present in 51% of infection-site cultures. Of 119 S.

aureus isolates (from infection site and nares), 89 (75%) were

MRSA, and almost all (99%) of the MRSA isolates possessed the

staphylococcal cassette chromosome (SCC) mec type IV allele

(typical of community-associated MRSA). Among predictor var-

iables independently associated with MRSA infection, the stron-

gest was presence of furunculosis (OR, 28.6). In this urban pop-

ulation, MRSA was the leading pathogen in SSTIs [16].

The CDC and 3 sites participating in the Emerging Infections

Program began a specialized, prospective MRSA surveillance

project in 2001 using the Active Bacterial Core Surveillance

program, a population-based surveillance component of the

Emerging Infections Program Network designed to study the

epidemiologic features of invasive bacterial disease and to track

drug resistance in the United States. The MRSA Active Bacterial

Core Surveillance project monitored all MRSA isolates from all

body sites from patients in select hospitals in Baltimore, Atlanta,

and Minnesota. From 2001 through 2002, 1647 cases of com-

munity-acquired MRSA infections were reported, and 77% in-

volved skin and soft tissue. Overall, 23% of patients were hos-

pitalized for the MRSA infection. This study concluded that

community-associated MRSA skin infections were now a com-

mon problem [17].

A prospective multicenter study confirmed this finding.

Adult patients with acute, purulent SSTIs presenting to 11 uni-

versity-affiliated emergency departments during the month of

August 2004 were enrolled to determine the causative bacterial

isolates. S. aureus was isolated from 320 (76%) of 422 patients

with SSTIs. The prevalence of MRSA was 59% overall, and USA

300 isolates accounted for 97% of MRSA isolates; SCC mec

type IV and the Panton-Valentine leukocidin toxin gene were

detected in 98% of MRSA isolates, consistent with community-

associated MRSA infection. Methicillin-susceptible S. aureus

(MSSA) was identified in only 17% of patients with SSTIs. In

this study, MRSA was the most common identifiable cause of

SSTIs among patients presenting to emergency departments in

11 US cities [18].

None of these studies specifically differentiate between the

epidemiologic characteristics of community-associated (i.e.,

with no established risk factors) versus health care–associated

(i.e., with health care–associated risk factors) SSTIs. They do,

however, address the issue of differences in the microbiological

characteristics between the community-associated and health

care–associated MRSA isolates (table 4) [19].

An active, prospective, laboratory surveillance study con-

ducted at a 1000-bed urban hospital and its affiliated outpatient

clinics in Atlanta, Georgia, identified S. aureus that was recov-

ered from SSTIs in 384 persons and 389 episodes of infection,

with MRSA accounting for 72% (279 of 389 episodes). Among

all S. aureus isolates, 63% (244 of 389 isolates) were commu-

nity-acquired MRSA. Among MRSA isolates, 87% (244 of 279

isolates) were community-acquired MRSA, and 99% were USA

300 clones. Factors independently associated with community-

acquired MRSA infection were black race (prevalence ratio,



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Table 4. Comparison of community-associated and health care–associated methicillin-resistantStaphylococcus aureus (MRSA).

Characteristic Community-associated MRSA Health care–associated MRSA

Susceptibility, drugChloramphenicol Usually susceptible Frequently resistantClindamycin Usually susceptible Frequently resistantErythromycin Usually resistant Usually resistantFluoroquinolone Geographic variability Usually resistantTMP-SMZ Usually susceptible Usually susceptible

SCC mec type IV IILineage USA 300, USA 400 USA 100, USA 200Toxin producing More FewerPanton-Valentine leukocidin producing Common RareHealth care exposure Less frequent More frequent

NOTE. SCC, staphylococcal chromosome cassette; TMP-SMZ, trimethoprim-sulfamethoxazole. Adapted from [19].

1.53; 95% CI, 1.16–2.02), female sex (prevalence ratio, 1.16;

95% CI, 1.02–1.32), and hospitalization within the previous 12

months (prevalence ratio, 0.80; 95% CI, 0.66–0.97). Inadequate

initial antibiotic therapy was statistically significantly more

common among those with community-acquired MRSA (65%)

than among those with MSSA (1%) SSTI. This study concluded

that the community-acquired MRSA USA 300 clone was the

predominant cause of community-onset S. aureus SSTIs, and

therefore empirical use of agents active against community-

acquired MRSA is warranted for patients presenting with se-

rious SSTIs. The study setting was a 1000-bed, urban hospital

and its affiliated outpatient clinics in Atlanta, Georgia [20].

Epidemiology and microbiology of cSSTI. Because no pub-

lished data are available for health care–associated cSSTIs, we

reviewed recent studies that served as FDA registration trials

for antimicrobials used to treat cSSTI. In 2 randomized inter-

national trials involving 1092 patients with cSSTI, daptomycin

was compared with conventional antibiotics (penicillinase-re-

sistant penicillin or vancomycin). S. aureus was the leading

causative pathogen, isolated in ∼70% of patients; MRSA ac-

counted for only 10% of the S. aureus isolates. Streptococci

and enterococci were also common causative pathogens [21].

In another phase 3 cSSTI study, patients ( ) weren p 854

randomized to receive dalbavancin or linezolid. Baseline cul-

tures yielded at least 1 gram-positive pathogen for 550 patients

(64%; the microbiological intent-to-treat population). Of these,

90% presented with a single gram-positive pathogen. S. aureus

was predominant (89% of all patients). Of the S. aureus isolates,

278 (57%) of 492 were MRSA. Overall, 51% of patients pre-

sented with cSSTI that involved MRSA [22].

Two phase 3, double-blind studies randomized hospitalized

adults with cSSTI to receive tigecycline or vancomycin-az-

treonam ( ). S. aureus, with a majority of isolates beingn p 1116

MSSA, was the leading pathogen, and streptococci were also

common. Gram-negative isolates (only E. coli) were uncommon

and were isolated in only 59 patients [23].

Two large, multinational, double-blind, randomized, phase 3

clinical studies (ATLAS 1 and ATLAS 2) enrolled 1867 patients

with cSSTI, 719 of whom were infected with MRSA, and deter-

mined that televancin was not inferior to vancomycin. S. aureus

was the primary pathogen isolated in these studies, as it was in

the 2 prior phase 2 trials (FAST 1 and FAST 2) [24–26].

A multicenter, global, randomized, double-blind trial com-

pared ceftobiprole with vancomycin for patients ( )n p 784

with cSSTI and confirmed the noninferiority of ceftobiprole,

and S. aureus was the primary causative isolate [27]. A second

cSSTI trial also included patients with diabetic foot infections,

and gram-negative pathogens were more common. Gram-pos-

itive pathogens were isolated from 79% of patients and MRSA

was the most common pathogen (42.4%). Gram-negative path-

ogens were isolated from 29% of patients, and E. coli (11.0%)

and Pseudomonas isolates (6.6%) were the most common [28].

All these studies confirm that the most common causative

pathogens in cSSTIs are aerobic gram-positive cocci, with S.

aureus and MRSA as the leading isolates.

Epidemiology and microbiology of surgical-site infections.

Surgical-site infections are also included in the cSSTI category.

In a report from the National Nosocomial Infections Surveil-

lance System from 1986–2003, an analysis of 1410,000 bacterial

isolates associated with hospital-acquired infections (BSIs,

pneumonia, surgical-site infection, and urinary-tract infection)

in intensive care units (ICUs) were reported. For surgical-site

infections, the percentage of bacterial isolates that were gram

negative decreased during the study period (from 56.5% in

1986 to 33.8% in 2003). By the mid-1990s, gram-positive bac-

terial pathogens were more commonly reported as causative

isolates in surgical-site infections, with S. aureus as the leading

pathogen [9]. MRSA has emerged as the most common isolate



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Figure 1. Voting comparison for statement 1 (“Patients at risk for health care–associated complicated skin and soft tissue infections are morelikely to have both resistant gram-negative and gram-positive pathogens”). “IDSA” refers to the members of the Infectious Diseases Society of Americawho responded to a Web-based survey; “Summit” refers to the Health Care–Associated Infection Summit panel.

causing surgical-site infections in most institutions [29]. MRSA

surgical-site infections are associated with significantly in-

creased mortality (OR, 3.4; ), length of hospital stay,P p .003

and costs, compared with MSSA surgical-site infections [30].

Community-associated MRSA strains are increasingly recov-

ered from hospital settings, and a recent retrospective review

of surgical-site infection in 2004–2005 in Alabama determined

that 57% of MRSA strains from surgical-site infections were of

the USA 300 genotype, confirming that community-associated

MRSA was a prominent cause of surgical-site infection at that

institution [31].

Epidemiology and microbiology of diabetic foot infection.

The bacteriology of diabetic foot infections was assessed in a

recent study of 371 patients (infected ulcer and cellulitis were

the most common types of infection). Overall, one-half of all

patients had only gram-positive cocci isolated (355 isolates).

Of these, S. aureus, coagulase-negative staphylococci, strepto-

cocci, and enterococci were the most common isolates. Gram-

negative bacteria, predominantly Pseudomonas and Enterobac-

teriaceae species, were isolated in 105 patients, and 32% had

mixed infections with both gram-positive and gram-negative

pathogens [32]. In the SIDESTEP study (of ertapenem vs. pi-

peracillin/tazobactam for treatment of diabetic foot infection;

), infections were polymicrobial in 47% of evaluablen p 586

patients, and 9% had both gram-positive and gram-negative

aerobic organisms isolated by culture. The most commonly

isolated pathogens were gram-positive aerobic cocci (257 iso-

lates), with S. aureus as the leading isolate, followed by gram-

negative aerobic bacilli isolates (102 isolates), with Enterobac-

teriaceae species as the leading isolates [33].

The IDSA guidelines for diagnosis and treatment of diabetic

foot infection state, “Aerobic gram-positive cocci (especially S.

aureus) are the predominant pathogens in diabetic foot infec-

tions. Patients who have chronic wounds or who have recently

received antibiotic therapy may also be infected with gram-

negative rods, and those with foot ischemia or gangrene may

have obligate anaerobic pathogens” [34, p. 885].

Grading of Evidence

On the basis of a review of the studies cited above, the workshop

members agreed that there was substantial evidence available

to reject this statement. In evaluating the nature of the evidence,

20% voted category I, 60% voted category II, and 20% voted

category III (table 3).

Level of Support

When voting on the individual level of support for this statement,

0% of the summit participants voted to accept the statement

completely, 18% voted to accept the statement with some res-

ervations, 9% voted to accept the statement with major reser-

vations, 45% voted to reject the statement with reservations, and

27% voted to reject the statement completely. In comparison, of

the 744 IDSA members who participated in the online survey,

32% voted to accept the statement completely, 42% voted to

accept the statement with some reservations, 11% voted to accept

the statement with major reservations, 12% voted to reject the

statement with reservations, and 3% voted to reject the statement

completely (figure 1).

Discussion

Presently, there is no true category or definition of health care–

associated cSSTI, and no studies were identified in the published

literature. The traditional categories of SSTI include uncompli-

cated versus complicated (initially proposed by the FDA for the

conduct of clinical trials for SSTIs) and community acquired or

community onset versus hospital acquired or nosocomial.

The leading causative pathogen of SSTIs in both community

and hospitalized patients is MRSA. This has been confirmed

with an in-depth review of the recent registration trials for

cSSTIs that discusses the microbiology of new antimicrobials

(daptomycin, dalbavancin, telavancin, tigecycline, and cefto-

biprole). S. aureus was the leading pathogen in all studies, with

rising rates of MRSA. The SENTRY Antimicrobial Surveillance

Program has documented that the rate of MRSA in SSTIs in



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Table 5. Definitions used for epidemiologic classification of invasive methicillin-resistantStaphylococcus aureus (MRSA) infections.

Classification Definition

Health care associatedCommunity onset Cases with at least 1 of the following health care risk factors: (1)

presence of an invasive device at time of admission; (2) historyof MRSA infection or colonization; (3) history of surgery, hospitali-zation, dialysis, or residence in a long-term-care facility in previ-ous 12 months preceding culture date

Hospital onset Cases with positive culture result from a normally sterile site ob-tained 148 h after hospital admission. These cases might alsohave �1 of the community-onset risk factors.

Community associated Cases with no documented community-onset health care risk factor

NOTE. Reprinted from JAMA 2007;298:1763–71 [39]. Copyright �2007, American Medical Association.All rights reserved.

North America increased substantially, from 26.2% of isolates

in 1998 to 47.4% of isolates in 2004. Community-associated

MRSA is the primary pathogen in patients without health care–

associated risk factors. S. aureus is also the leading pathogen

in surgical-site infections, with rising rates of MRSA.

Given the high prevalence of MRSA cSSTI at present, is it

important to standardize the classification of these invasive

MRSA infections? Several methods are used to classify MRSA

as health care associated or community associated, including

(1) genotypic testing, based on the results of PFGE or other

molecular techniques; (2) phenotypic testing, based on anti-

microbial susceptibility testing; and (3) epidemiologic analysis,

based on the time from hospital admission to a positive culture

result. Definitions of community-associated MRSA often use

time-based criteria in which the recovery of MRSA isolates

within 48 or 72 h after hospital admission is considered in-

dicative of community-associated MRSA. However, time-based

criteria do not consider patients with MRSA infection after

recent health care exposure. Furthermore, community-associ-

ated MRSA has emerged as a health care–associated and nos-

ocomial pathogen [35–38]. Community-associated MRSA

strains differ from hospital-acquired MRSA strains in that they

are generally susceptible to most antibiotics, whereas nosoco-

mial strains are generally multidrug resistant (MDR). However,

these data are not available to the prescribing clinician when

empirical antibiotics are selected.

The recent epidemiologic reports of invasive MRSA infec-

tions ( ) in the United States, which were associatedn p 8987

with 1598 in-hospital deaths, classified cases into mutually ex-

clusive groups (health care associated vs. community associ-

ated), first on the basis of health care risk factors. HAIs, in

turn, were classified as either community onset or hospital onset

(table 5) [39].

In contrast, in diabetic foot infections, gram-negative path-

ogens and polymicrobial infections are more common than are

surgical-site infections and cSSTIs. There are, however, some

additional cSSTI categories in which resistant gram-positive and

gram-negative pathogens would be likely. These include peri-

neal infections, necrotizing soft-tissue polymicrobial infections,

pressure ulcer and decubitus infections, and surgical-site in-

fections related to abdominal and genitourinary surgical

procedures.

Future Directions

Future directions discussed by the summit members include

the need to evaluate whether a category of health care–asso-

ciated cSSTIs is appropriate at this time. The use of HAI cat-

egories in bacteremia and pneumonia are thought to be im-

portant for improving the recognition of those patients who

may be infected with MDR pathogens and therefore warrant

more broad-spectrum empirical antimicrobial therapy. There

is minimal evidence to suggest that the addition of health care–

associated cSSTIs would have significant implications for the

selection of empirical antimicrobial therapy for these patients

with skin infections. Other potential classification schemes

could be considered for cSSTIs, such as monomicrobial versus

polymicrobial, necrotizing versus nonnecrotizing, and pyogenic

versus nonpyogenic. Additional detailed studies of SSTIs are

warranted to further delineate changes in the microbial etiology

of cSSTIs, to optimize treatment strategies and also to evaluate

risk factors for recurrence.

STATEMENT 2: PATIENTS WITH HEALTH CARE–ASSOCIATED INTRA-ABDOMINAL INFECTIONSSHOULD RECEIVE DUAL EMPIRIC THERAPYFOR RESISTANT GRAM-NEGATIVE AND GRAM-POSITIVE PATHOGENS


Complicated intra-abdominal infections (cIAIs) are defined as

infections that extend beyond the hollow viscus of origin into

the peritoneal space and are associated with either abcess for-



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mation or peritonitis [40]. Intra-abdominal infections pose se-

rious challenges to the treating physicians, and mortality rates

approach 60% [41]. Rapid diagnosis, appropriate intervention,

and timely and efficacious anti-infective therapy are of critical

importance and have been shown to lead to improved patient

outcomes.

The traditional binary classification scheme for cIAIs has

consisted of nosocomial and community-acquired infections.

At present, there is no defined category for health care–asso-

ciated cIAI, unlike the distinction that has been made recently

with BSI and pneumonia. Many of the data regarding epide-

miology and antimicrobial treatment of cIAI are derived from

antimicrobial trials, and most patients who entered into those

trials had community-acquired infections, such as perforated

or complicated appendicitis, and have not been severely ill.

It is estimated that ∼80% of all intra-abdominal infections

(IAIs) are acquired in a community setting [42]. In com-

munity-acquired infections, the location of the gastrointes-

tinal perforation defines the infecting flora: infections that

occur beyond the proximal small bowel are caused by fac-

ultative and aerobic gram-negative organisms; infections that

occur past the proximal ileum can be caused by a variety of

anaerobic microorganisms.

The IDSA guidelines for cIAI used the term “health care–

associated infections” to describe nosocomial infections, in-

cluding cIAIs acquired postoperatively. HAIs were specifically

defined as infections that “are most commonly acquired as

complications of previous elective or emergent intra-abdominal

operations and are caused by nosocomial isolates particular to

the site of the operation and to the specific hospital and unit”

[40, p. 997].

In the context of the HAI Summit’s reference to other in-

fections, the term HAI was used to describe infections in in-

dividuals who regularly interact with the health care environ-

ment. It has been suggested that HAIs represent a unique

population of patients. These patients are thought to be infected

not only with a different spectrum of pathogens but also with

potentially more-resistant flora.

The term HAI was first used to characterize a spectrum of

BSIs [6]. Similarly, patients with cIAI with these same risk

factors for HAI may have ample opportunity to acquire resis-

tant bacteria. It is undetermined at present whether an ex-

panded classification scheme, to include health care–associated

cIAI, may be necessary for patients with IAIs. There is currently

no standard category or definition for HAIs in the broader

category of IAIs.

This review focuses on the available literature that charac-

terizes the microbiology of cIAIs (both community acquired

and nosocomial), the importance of appropriate initial empir-

ical therapy, and the incidence of MDR organisms. By assess-

ment of the strength of this evidence, it is possible to ascertain

whether an expanded classification system that includes health

care–associated cIAI is needed and would benefit a potential

new subgroup of patients.

Methods

A PubMed database search was conducted on 4 September 2007

to identify relevant reports involving the treatment and mi-

crobiological features of health care–associated IAIs. The search

term “intra-abdominal infections” yielded a total of 2347 ar-

ticles. The search terms “health care associated,” “healthcare-

associated,” and “healthcare associated” yielded 51,504, 38,460,

and 288 articles, respectively. When these terms were combined

with “intra-abdominal infections,” using the “AND” function,

22 articles were found. After the results were limited to the

English language, 0 articles were found to be relevant to the

statement.

In a second PubMed database search, the search term “post-

operative peritonitis OR secondary peritonitis” yielded 9237

articles. This term was combined with “microbiology,” using

the “AND” function, yielding 168 articles; with the search term

“drug resistance,” yielding 198 articles; and with the search term

“appropriate therapy,” yielding 220 articles. After results were

limited to humans and the English language, 5 articles were

found to be relevant to the statement. The IDSA and the Sur-

gical Infection Society guidelines for the treatment of cIAIs were

also reviewed.

Evidence

No studies specifically related to “health care–associated intra-

abdominal infections” were identified. The 2 issues of empirical

antibiotic therapy and dual empirical therapy for treatment of

infection with resistant gram-positive and gram-negative path-

ogens will be addressed separately.

Empirical antimicrobial therapy for cIAI. The first portion

of the statement recommends that patients with health care–

associated IAI should receive empirical antimicrobial therapy.

A retrospective case study by Krobot et al. [43] assessed the

effect of inappropriate initial empirical antibiotic therapy in

425 patients with “community-acquired” secondary peritonitis.

E. coli was the most commonly isolated pathogen. A total of

54 patients (13%) received inappropriate initial therapy. Clin-

ical success, predefined as resolution of infection with initial

or step-down therapy after primary surgery, was achieved for

322 patients (75.7%). However, patients were more likely to

have clinical success if the initial antibiotic therapy was appro-

priate than if it was inappropriate (75.7% vs. 53.4%). Patients

who had clinical success had a mean length of stay of 13.9

days, compared with 19.8 days for those who had clinical fail-

ure. Furthermore, multinomial analyses (with adjustment for

patient age, sex, and comorbidities) revealed that inappropriate



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antimicrobial therapy was associated with the need for second-

line antibiotic therapy and repeated operation.

A more recent multicenter study of 425 patients with com-

munity-acquired IAI in Spain examined the consequences of

inappropriate initial empirical parenteral antibiotic therapy

[44]. Initial empirical therapy was classified as appropriate if

all isolates were susceptible to at least 1 of the antibiotics ad-

ministered. A total of 387 patients (92%) received appropriate

initial empirical therapy. Patients receiving inappropriate ther-

apy were less likely to have clinical success (79% vs. 26%;

), more likely to require additional antibiotic therapyP ! .001

(40% vs. 7%; ), and more likely to be rehospitalizedP ! .01

within 30 days after discharge (18% vs. 3%; ). Multi-P ! .01

variate analyses also showed that inappropriate therapy was

associated with an almost 16% increase in length of stay and

a 26% increase in the number of days of antibiotic therapy.

Inappropriate initial antibiotic therapy was associated with a

significantly higher proportion of unsuccessful patient out-

comes, including death, repeated operation, rehospitalization,

additional antibiotic therapy, and increased length of stay. Other

studies have confirmed similar findings [45–47]. These data

clearly confirm that patients with IAI should receive appropriate

empirical antimicrobial therapy.

Dual empirical antimicrobial therapy for cIAI with resis-

tant gram-positive and gram-negative pathogens. The sec-

ond portion of the statement recommends that dual empirical

therapy for resistant gram-positive and gram-negative patho-

gens should be used for patients with health care–associated

cIAI.

The IDSA guidelines for cIAI separate the recommendations

regarding selection of anti-infective agents into 2 categories—

“mild-to-moderate” and “high-severity” infections—and these

may occur in both patients with community-acquired and pa-

tients with nosocomial infections [40]. Similarly, the Surgical

Infection Society guidelines for cIAI separate the recommen-

dations into “lower-risk patient” and “higher-risk patient” [48].

In general, for less severely ill patients with community-ac-

quired infections, antimicrobial agents with a narrow spectrum

of activity are adequate.

The IDSA recommends that community-acquired infections

may be managed with a variety of single- and multiple-agent

therapeutic regimens that are based, in part, on in vitro activ-

ities. The IDSA advises that no particular antimicrobial regimen

has consistently been demonstrated to be superior or inferior

(table 6).

For higher-risk patients or for those with high-severity IAIs,

broader-spectrum empirical antimicrobial therapy is recom-

mended to cover potential MDR pathogens. Nosocomial IAIs

are typically caused by a more-resistant flora, which may in-

clude P. aeruginosa, Acinetobacter species, Enterobacter species,

Proteus species, MRSA, enterococci, and Candida species. The

IDSA’s treatment recommendations for nosocomial cIAI sug-

gest multidrug regimens guided by knowledge of nosocomial

flora and susceptibility patterns.

Several studies have documented that infections involving

resistant organisms, particularly those likely to be acquired in

the health care setting, are associated with an increased risk of

treatment failure, morbidity, and mortality [49–52]. Prolonged

preoperative length of stay and prolonged (12 days) preoper-

ative antimicrobial therapy are significant predictors of anti-

microbial failure leading to recurrent infection, which suggests

that organisms resistant to the empirical antimicrobial regimen

may be responsible for infection. Patients with these risk factors

should be given treatment for nosocomial infection.

Montravers et al. [52] evaluated the incidence of resistant

bacterial strains among patients with postoperative peritonitis,

as well as the efficacy of empirical antimicrobial therapy. In

this study, 100 resistant pathogens were isolated from 70 pa-

tients who underwent repeated operation for generalized post-

operative peritonitis. Candida species and both gram-negative

and gram-positive anaerobic bacteria were isolated (table 7)

[52]. The relative frequencies of different pathogens cultured

in this patient population differed from those typically found

in patients with “community-acquired peritonitis.” Further-

more, the authors determined that 54% of the patients who

received inadequate initial empirical therapy for these resistant

pathogens had poorer outcomes, compared with patients who

received adequate therapy ( ).P ! .05

Roehrborn et al. [53] examined the microbiology of postop-

erative peritonitis in a prospective case study involving 67 pa-

tients. The most common isolates from patients with postop-

erative peritonitis were E. coli and Enterococcus, Enterobacter,

Bacteroides, and Klebsiella species. In addition, patients with post-

operative peritonitis were significantly more likely than were pa-

tients with community-acquired infections to have the following

isolates: enterococci (23 vs. 6), Enterobacter species (13 vs. 4), S.

aureus (7 vs. 1), and coagulase-negative staphylococci (7 vs. 1).

Patients with community-acquired infections were significantly

more likely to have streptococci and E. coli isolated.

The Study for Monitoring Antimicrobial Resistance Trends,

begun in 2002 and developed by the Merck research program,

is designed to monitor resistance patterns among aerobic and

facultative gram-negative bacilli isolated worldwide from intra-

abdominal bacterial clinical isolates collected from multiple

centers (including both teaching and community hospitals)

[54]. Data from the 2004 report [55] were used in the evaluation

of 6156 unique aerobic and facultatively anaerobic gram-neg-

ative bacilli isolated from IAIs. Enterobacteriaceae composed

86% of the total isolates, with E. coli (48%), Klebsiella species

(16%), and Enterobacter species (9%) comprising the majority

of isolates. Quinolone susceptibility rates for E. coli were sig-

nificantly reduced (60%–70% susceptible), with the lowest rates



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Tabl

e6.

Ther

apeu

ticre

gim

ens

for

com

plic

ated

intr

a-ab

dom

inal

infe

ctio

ns,a

ccor

ding

togu

idel

ines

from

the

Infe

ctio

usD

isea

ses

Soci

ety

ofA

mer

ica

(IDSA

)and

the

Surg

ical

Infe

ctio

nSo

ciet

y(S

IS).

Cla

ssifi

catio

n

Sin

gle

agen

tC

ombi

natio

nre

gim

en

IDS

AS

ISID

SA

SIS

Low

risk

(cat

egor

ized

as“m

ild-t

o-m

oder

ate

infe

ctio

ns”

byth

eID

SA

and

“low

er-r

isk

patie

nts”

byth

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IS)

Am

pici

llin/

sulb

acta

ma

Tica

rcill

in/c

lavu

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Am

pici

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nic

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erop

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ycin

Third

/fou

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gene

ratio

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rinc

plus

anan

tiana

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min

ogly

cosi

ded

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eH

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risk

(cat

egor

ized

as“h

igh-

se-

verit

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Aan

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)

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amIm

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atin

Mer

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sing

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stan

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and

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cept

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typr

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ould

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view

edbe

fore

use.

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.



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Table 7. Organisms reported in a study of postoperative peri-tonitis by Montravers et al. [52].

OrganismNo. of

isolates

Gram negativeEscherichia coli 53Proteus/Morganella species 25Pseudomonas species 21Klebsiella species 14Enterobacter cloacae 10Acinetobacter/Citrobacter/Serratia species 10

Gram positiveMethicillin-resistant Staphylococcus species 24Enterococcus faecalis 19Enterococcus faecium 19

AnaerobeBacteroides species 13Candida species 23

NOTE. Adapted from [52], with permission from the University of ChicagoPress. Some patients had 11 isolate.

in the Asia/Pacific region and Latin America. Extended-spec-

trum b-lactamases (ESBLs) were detected phenotypically in

10% of E. coli, 17% of Klebsiella species, and 22% of Entero-

bacter species worldwide, representing an increase from the 2

previous years.

In this large surveillance program, an additional analysis of

7002 E. coli isolates documented that increasing resistance rates

have been seen in both community-acquired and hospital-ac-

quired E. coli infections [56]. Ampicillin-sulbactam was the least

active agent (45.1%–67.6% of isolates were susceptible). Quin-

olones (ciprofloxacin and levofloxacin) also demonstrated low

activity (69%–75% susceptible). E. coli isolated !48 h after

hospital admission (presumed to be community acquired) were

more often susceptible to the agents tested than were E. coli

isolated 148 h after hospitalization (presumed to be hospital

acquired). There were small differences in susceptibility rates

between community-acquired and hospital-acquired E. coli for

the carbapenems and amikacin, but there were more sizable

differences for other agents, including ampicillin-sulbactam

(60.3% vs. 48.4%), ciprofloxacin (83.7% vs. 71.6%), and levo-

floxacin (83.8% vs. 73.5%). Antimicrobial resistance among

gram-negative bacteria isolated from IAIs, both community

acquired and nosocomial, is emerging as a more significant

problem worldwide.

Although resistance rates are of growing concern, there are

rare studies that examine the consequences of resistance and

adequate empirical treatment for outcomes. A retrospective co-

hort study by Peralta et al. [57] analyzed patients with E. coli

bacteremia to identify associations between antibiotic resistance,

adequacy of empirical therapy, and mortality. Of the 663 patients

included in the study, those with MDR E. coli bacteremia had a

significantly lower frequency of correct empirical treatment than

did patients with non-MDR E. coli bacteremia (relative risk [RR],

0.53; 95% CI, 0.48–0.67), coupled with a considerably higher

mortality rate (RR, 3.31; 95% CI, 1.72–6.36).

A prospective observational study by Seguin et al. [58] re-

ported factors associated with MDR bacteria in secondary peri-

tonitis. Forty-four cases of community-acquired peritonitis and

49 cases of nosocomial peritonitis (35 postoperative cases) were

reported. In univariate analysis, the risk of acquiring an MDR

organism was significantly associated with a higher Acute Phys-

iology and Chronic Health Evaluation (APACHE) II score. In

addition, preoperative length of hospital stay, previous anti-

microbial therapy, and the duration and modification of post-

operative antimicrobial therapy were significantly associated

with the presence of MDR bacteria. Multivariate analysis confir-

med that patients with a preoperative length of hospital stay

of �5 days had a higher risk for developing an MDR IAI,

especially if antibiotics had been used previously. The authors

concluded that knowledge of these 2 risk factors for acquiring

MDR bacteria (preoperative length of stay and prior use of

antibiotics) enables the use of expanded-spectrum empirical

antimicrobial therapy for these specific high-risk patients.

No studies were identified that specifically focused on the

epidemiology and/or incidence of MDR organisms of “health

care–associated” IAIs. Additional discussion regarding the po-

tential definition of health care–associated IAIs and patients

who would be included in such a category suggested that it

could include patients with cIAIs such as peritoneal dialysis-

catheter infections, patients with spontaneous bacterial peri-

tonitis with multiple prior episodes, and patients in nursing

homes or long-term-care facilities who develop cIAIs including

appendicitis, cholecystitis, and diverticulitis. There is no con-

sensus as to whether this category of “health care–associated

cIAI” should be created.

Grading of Evidence


members agreed that there was substantial evidence to accept

the statement. In evaluating the nature of the evidence, 40%

voted category II, 20% voted category III, and 40% voted cat-

egory IV (table 3).

Level of Support

When voting on the support for this statement, 0% of the

summit participants voted to accept the statement completely,

27% voted to accept the statement with some reservations, 64%

voted to accept the statement with major reservations, 9% voted

to reject the statement with reservations, and 0% voted to reject

the statement completely. In comparison, of the 744 IDSA

members who participated in the online survey, 30% voted to

accept the statement completely, 38% voted to accept the state-



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Figure 2. Voting comparison for statement 2 (“Patients with health care–associated intra-abdominal infections should receive dual empiric therapyfor resistant gram-negative and gram-positive pathogens”). “IDSA” refers to the members of the Infectious Diseases Society of America who respondedto a Web-based survey; “Summit” refers to the Health Care–Associated Infection Summit panel.

ment with some reservations, 11% voted to accept the state-

ment with major reservations, 18% voted to reject the statement

with reservations, and 3% voted to reject the statement com-

pletely (figure 2).

Discussion

In summary, a review of the literature produced very limited

retrospective studies in general support of the statement. How-

ever, in practice, patients suspected of having risk factors for

a “health care–associated” infection typically receive empirical

therapy for MDR gram-positive and gram-negative organisms.

On the basis of the presented studies of patients with secondary

peritonitis, it is reasonable to assume that certain patient sub-

groups were infected with a different spectrum of bacteria, as

well as with MDR bacteria. The current studies of patients with

secondary peritonitis document that appropriate empirical an-

tibiotic coverage as well as coverage for MDR organisms lead

to improved outcomes.

Future Directions

Traditional categorization of IAIs has segregated them as nos-

ocomial or community-acquired infections. In recent years,

epidemiologic studies have identified that pathogens associated

with cIAI demonstrate rising levels of drug resistance in both

groups. It has also been shown that inadequate initial empirical

therapy is associated with a significantly higher rate of failures

and death. On the basis of studies of patients with postoperative

peritonitis, it is reasonable to suggest that select patients may

benefit from broad-spectrum empirical therapy. For patients

with peritonitis, several attempts have been made to identify

clinical features that increase the risk of adverse outcomes. For

these patients, the IDSA suggests that antimicrobial regimens

with expanded spectra may be warranted. Finally, given the

different spectrum of pathogens and the varying levels of re-

sistance seen in patients with peritonitis, an effort should be

made to identify other patient types and specific risk factors

for IAIs due to resistant pathogens. Because unnecessary broad-

spectrum therapy is associated with its own problems, caution

should be exercised. Future studies will need to be conducted

to examine whether health care–associated cIAI should be de-

lineated as a separate category of IAIs before specific recom-

mendations can be made.

STATEMENT 3: EARLY AGGRESSIVE,APPROPRIATE EMPIRIC TREATMENTAND DE-ESCALATION FOR HCAP REDUCESMORTALITY AND MINIMIZES RESISTANCE


A designation of “health care–associated” infection was first

used for cases of bacteremia in which patients who acquired

bacteremia as outpatients were found to have pathogens usually

associated with hospital-acquired infections [6]. Of significance,

the term referred only to patients who were hospitalized with

an infection, not to those who remained in their nonhospital

setting. The term “health care associated” seemed to apply to

a variety of infections, including pneumonia, with a similar

propensity to be caused by typically nosocomial pathogen. The

concept of HCAP was therefore readily embraced. For this

reason, HCAP was included in the latest statement on HAP

from the ATS and IDSA [1] and was essentially excluded from

discussion in the recent IDSA-ATS consensus guidelines on the

management of CAP [2].

Because several principals of treatment have been thought

to be important for outcomes among patients with HAP and

VAP, logic would suggest that these principals are applicable to

HCAP as well. These principals include: (1) early initiation of

empirical antibiotic treatment; (2) use of broad-spectrum, em-

pirical, antibiotic therapy to avoid inappropriate therapy; and

(3) narrowing or “de-escalation” of empirical antibiotic therapy

on the basis of results of respiratory-tract cultures [1]. The

purported benefits of such an approach were to decrease the

mortality associated with inappropriate initial antibiotics while,

at the same time, lessening the emergence of antibiotic-resistant



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pathogens. Although it may be logical to assume that these

principals and expected results apply to HCAP, this section aims

to assess the strength of evidence supporting this assertion.

Methods

A PubMed search was performed on 1 October 2007. With the

search limited to the English language, the term “health care

associated OR healthcare associated OR health care-associated

OR healthcare-associated” gave a total of 33,408 articles. This

result combined with the term “pneumonia” resulted in a total

of 333 articles. This result combined with the term “treatment”

yielded 309 articles. The abstracts were reviewed for pertinence,

and additional “related articles” were also screened. The text

word “antibiotic” was also combined with the 333 health care–

associated/pneumonia articles, resulting in 87 common articles.

Abstracts of all these articles were examined, as were the “related

articles” for each. One apposite article was found.

As a consequence of the overlap of HCAP with other pneu-

monia terms, additional searches were performed. Combina-

tion of the terms “nursing home AND pneumonia AND treat-

ment” resulted in 262 English language articles and 1 relevant

article.

Evidence

No randomized, controlled trials of treatment specific to hos-

pitalized patients with HCAP were found. No concurrent co-

hort studies of antibiotic treatment in general for hospitalized

patients with HCAP were found. Only 1 randomized, controlled

trial involving nursing home patients that specifically addressed

treatment in the nursing home was available [59].

No category I evidence for any aspect of the statement.

Because the entity of HCAP has been defined only recently,

studies of either CAP or HAP may have bearing on the state-

ment; therefore, this evidence will also be reviewed. Further-

more, because the statement is multifaceted, each statement

component will be discussed separately.

Appropriate empirical therapy. Only 1 study specifically

addressed the issue of appropriate empirical therapy for HCAP

[59]. This was a preintervention and postintervention study of

the management of nursing home–acquired pneumonia with

either oral or parenteral antibiotic therapy. The actual inter-

vention was a guideline for the indication for parenteral an-

tibiotics in a randomized study of 10 skilled-nursing facilities

involving either a multidisciplinary or a physician-only training

program. After the intervention, use of parenteral antibiotics,

when indicated by guidelines, increased significantly ( )P ! .02

without differences by randomization. No overall mortality

benefit was seen. Emergence of resistance was not addressed.

Because 35%–40% of patients ultimately required hospitali-

zation, the results have some pertinence to the issue of HCAP.

The issue of appropriate antibiotic therapy for HCAP re-

volves around the microbial etiology of HCAP, specifically

whether broad-spectrum antibiotic therapy is needed to em-

pirically cover MDR pathogens, such as P. aeruginosa, MRSA,

and ESBL-producing Enterobacteriaceae. Surprisingly, only 3

epidemiologic studies address this issue specifically. Two ret-

rospective US studies focused on culture-positive cases; the first

study examined a large administrative database [7], and the

second analyzed a single large tertiary care referral hospital [8].

Both studies demonstrated that HCAP was more common than

CAP, with a high frequency (20%–25%) of each of the MDR

pathogens listed above. Conversely, another study involving a

Spanish, multicenter, prospective, observational cohort of pa-

tients admitted with pneumonia found that only 17.3% of cases

could be classified as HCAP and that the incidences of cases

of pneumonia caused by gram-negative organisms (other than

Legionella species and Hemophilus influenzae, typical CAP path-

ogens) and S. aureus were both !5% [60]. However, 32% of

patients with HCAP in this study did not receive a microbi-

ological diagnosis, and an additional 20% received a diagnosis

of aspiration pneumonia, which left a positive microbiological

diagnosis for !50%.

Several explanations for these major differences in etiology

of HCAP exist. By far the most important is the inclusion of

HCAP cases without a microbiological diagnosis. Others in-

clude differences in criteria (all immunocompromised patients

included vs. only severely immunocompromised patients in-

cluded; previous hospitalization in the past 12 months vs. the

past 3 months), different types of hospitals (major referral cen-

ters vs. smaller local hospitals), and study design (retrospective

vs. prospective).

Even if MDR pathogens occur at high frequency, the use of

broad-spectrum therapy is still of unclear benefit with regard

to mortality. Two studies, both using the before-after interven-

tion format, specifically addressed this issue. Ibrahim et al. [61]

found that the use of a 3-drug, broad-spectrum protocol for

late-onset VAP was able to decrease the percentage of patients

administered inappropriate initial empirical antibiotic therapy

to 5.8%, as opposed to 52% before protocol introduction. Mor-

tality was unaffected, although the incidence of recurrent VAP

and subsequent infection with MDR pathogens decreased. The

second study [62], which used a similar type of empirical pro-

tocol, also demonstrated that the use of inappropriate initial

antibiotic therapy was decreased significantly, and broader-

spectrum therapy resulted in decreased mortality at 14 days

after treatment (27% vs. 8%; ). However, the statisticallyP p .03

significant reduction in mortality was not maintained for 30-

day or in-hospital mortality.

An additional article from the CAP literature on cases of

pneumonia caused by gram-negative pathogens from a pro-

spective CAP database was pertinent and thus was reviewed

[63]. Most patients with CAP caused by gram-negative path-



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ogens had risk factors that would likely qualify them for HCAP

status. Provision of appropriate initial therapy was not asso-

ciated with a significant improvement in mortality (32% vs.

13%; ).P p .27

In summary, despite being intuitively logical and supported

by multiple retrospective studies, no prospective study of VAP,

nursing home–acquired pneumonia, HCAP, or CAP has dem-

onstrated a mortality benefit from broader-spectrum proto-

colized antibiotic regimens, despite efforts made to consistently

decrease rates of inappropriate therapy to low levels. Thus, the

support for a mortality benefit of aggressive broad-spectrum

therapy for HCAP cannot even be extrapolated from studies

of other types of pneumonia.

Aggressive empirical therapy. The use of the broad-spec-

trum multiple-drug regimens discussed above can be considered

aggressive empirical therapy. However, the only published study

specifically addressing HCAP is a retrospective review of van-

comycin dosing for patients with HAP and HCAP [64]. The

authors compared dosing that was adjusted to achieve a serum

trough level of 115 mg/mL, as recommended by the ATS-IDSA

guidelines because of poor outcomes with standard dosing. The

group that achieved trough levels greater than this threshold did

not have a mortality benefit and had more adverse effects [65].

Early empirical therapy. The timing of appropriate antibi-

otic therapy has received significant attention. No study of HCAP

has specifically examined the timing of antibiotic therapy. How-

ever, 2 large retrospective reviews of Medicare patients suggested

a survival advantage when there was earlier provision of anti-

biotics [66, 67]. Many of these patients were likely to have HCAP.

Although significant differences in mortality among patients re-

ceiving antibiotics in the first 4–8 h were documented, the trend

toward increased mortality was heterogeneous, with some of the

highest mortality rates found among those who received anti-

biotics in the first 2 h after presentation to the emergency de-

partment. More importantly, prospective studies of CAP guide-

line implementation have demonstrated that mortality is

unchanged despite significant increases in the proportion of

patients receiving antibiotics within 4 or 8 h [68].

The only prospective trial involving VAP did not show a

difference in mortality if antibiotics were started empirically

when VAP was suspected, compared with when the culture

results were returned [69]. However, the study was limited to

trauma patients for whom an attributable mortality due to VAP

was unclear and VAP was less likely to have been caused by

MDR pathogens. Duration of ventilation was increased for pa-

tients randomized to receive culture-directed treatment. Ret-

rospective data from a medical ICU population suggest that a

delay of 24 h in initiating therapy is associated with excess

mortality [70].

The strongest evidence in favor of early antibiotic therapy is

from a retrospective review of septic shock, in which every 1-

hour delay in initiation of antibiotic therapy was associated

with a 7.6% increase in mortality [4]. In this study, 37% of

patients had pneumonia.

Early de-escalation of empirical therapy. De-escalation has

a variety of definitions. The most accepted definition is a de-

crease in the number of different antibiotics being used for

treatment; however, de-escalation may also include switching

to a narrower-spectrum agent, shortening the duration of ther-

apy, or even ceasing the administration of antibiotics altogether

when culture results are negative.

Both before-after antibiotic treatment protocols included de-

creasing the number of empirical antibiotics (once culture re-

sults were known), as well as the duration of use [61, 62].

Although neither protocol was associated with a mortality ben-

efit, the use of very-broad-spectrum antibiotics and de-esca-

lation was associated with a decrease in the subsequent occur-

rence of colonization or infection with MDR pathogens [61,

62, 71]. Some evidence of antibiotic pressure was seen in the

study by Soo Hoo et al. [62], in which 6 of the 7 imipenem-

resistant isolates occurred in patients given the more aggressive

empirical regimen (which included imipenem). Two additional

randomized trials are significant. Singh et al. [71] demonstrated

that, among patients with HAP or VAP who have a persistently

low clinical pulmonary infection score, the discontinuation of

antibiotic therapy after 3 days was associated with a decrease

in the percentage of pathogens that were MDR (14% vs. 38%;

) and a trend toward mortality differences. Chastre etP p .017

al. [72] demonstrated that patients with VAP randomized to

receive 8 days of therapy had lower rates of emergence of MDR

pathogens than did those who received 15 days of therapy

(42.1% vs. 62%; ). A randomized, controlled trial ofP p .04

diagnostic methods also demonstrated that, when fewer anti-

biotics were used, the 14-day mortality (16.2% vs. 25.8%;

) and severity-adjusted 28-day mortality were de-P p .022

creased, although no differences in the emergence of MDR

pathogens was demonstrated (61.3% vs. 59.8%; ) [73].P 1 .2

In summary, early de-escalation of therapy has an unclear

association with decreased mortality. The strongest support

comes from avoiding or discontinuing antibiotic therapy com-

pletely, rather than narrowing the spectrum or decreasing the

number of antibiotics. Conversely, any type of de-escalation is

associated with a decrease in the emergence of MDR pathogens.

The major benefit appears to occur with a decrease in the overall

duration of therapy, rather than de-escalation per se.

Grading of Evidence

On the basis of a review of the studies cited above, 83% of the

members of this workshop agreed that the nature of the evi-

dence available to support this statement was category II for

the statement in general, with the remainder grading the evi-

dence as category III (table 3).



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Figure 3. Voting comparison for statement 3 (“Early aggressive, appropriate empiric treatment and de-escalation for HCAP reduces mortality andminimizes resistance”). “IDSA” refers to the members of the Infectious Diseases Society of America who responded to a Web-based survey; “Summit”refers to the Health Care–Associated Infection Summit panel. HCAP, health care–associated pneumonia.

Level of Support


workshop members voted to accept the statement with some

reservations, and 45% voted to accept the statement with major

reservations. In comparison, of the 744 IDSA members who

participated in the online survey, 56% voted to accept the state-

ment completely, 36% voted to accept the statement with some

reservations, 5% voted to accept the statement with major res-

ervations, 2% voted to reject the statement with reservations,

and 1% voted to reject the statement completely (figure 3).

Discussion

The difference between the voting of the workshop participants

and that of the IDSA members is striking. The most likely

explanation is an overestimation of the literature support for

the concept of HCAP. Only 3 studies have specifically addressed

HCAP [7, 8, 60]. Most of the other information is extrapolated

from either HAP/VAP or CAP literature.

The second major issue is the over-reliance on retrospective

studies, which is particularly true for data on inappropriate

initial empirical therapy, for which multiple retrospective stud-

ies consistently show excess mortality among patients receiving

inappropriate initial empirical therapy [1]. The prospective tri-

als of broad-spectrum empirical therapy with de-escalation do

not demonstrate that providing appropriate initial antibiotics

is sufficient to improve mortality [61, 62]. One explanation for

this seemingly paradoxical finding between retrospective and

prospective trials is that antibiotics for MDR pathogens may

frequently be ineffective, despite being appropriate [1].

Another explanation may be that the patient’s host response

is unable to cure the pneumonia despite antibiotic therapy.

Here, the difference between CAP and HAP, especially VAP, is

likely to be great. Many VAP cases occur during a period of

relative immunoparalysis after initial ICU admission for a crit-

ical illness [74]. In contrast, most CAP cases are characterized

by a proinflammatory state. Although the pathogens associated

with HCAP may resemble HAP and/or VAP, it is unclear

whether the physiologic response will vary in the same way.

Future Directions

No prospective, randomized trial comparing appropriate versus

inappropriate initial antibiotic therapy for HCAP has been per-

formed. Therefore, the only information regarding the benefit

of early appropriate initial therapy will have to come from

studies of alternative empirical regimens, such as those for VAP.

Given the wide discrepancy in the frequencies of MDR path-

ogens in HCAP cases in recent studies, this type of study is

clearly needed.

STATEMENT 4: HEALTH CARE–ASSOCIATEDBSIs REQUIRE EMPIRIC COVERAGE FOR MDRGRAM-NEGATIVE BACTERIA AND MRSA,AS WELL AS COVERAGE FOR FUNGALPATHOGENS IN PATIENTSWITH SPECIFIC RISK FACTORS


BSI is a common and potentially lethal complication of health

care contact. A significant minority of hospitalized patients

develop a BSI. Among these patients, mortality rates are high.

This high mortality may be caused in part by the emergence

of antimicrobial resistance in pathogens associated with the

health care system. Such antimicrobial resistance increases the

possibility of inadequate empirical antimicrobial therapy, which

can delay the time until effective antimicrobial therapy is

administered.

The entity of health care–associated BSI was first defined by

Friedman et al. [6] as involving a positive culture result from

a blood specimen that was obtained from a patient within 48

h after admission if the patient received intravenous therapy,

wound care, or specialized nursing care or did any of the fol-

lowing: received self-administered intravenous medical therapy

in the 30 days before the BSI; attended a hospital or hemo-



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dialysis clinic or received chemotherapy in the 30 days before

the BSI; was hospitalized in an acute care hospital for �2 days

in the 90 days before the BSI; or resided in a nursing home or

long-term-care facility. A key finding of this study was that the

prevalence of antimicrobial-resistant pathogens among patients

with non-nosocomial health care–associated BSI (i.e., BSI that

did not originate in the hospital setting) resembled that among

patients with nosocomial BSI. Thus, for the purposes of the

present article, HAIs are defined as both nosocomial and non-

nosocomial HAIs.

Methods

A PubMed search related to health care–associated BSI was

completed on 28 September 2007. The search terms “health

care associated,” “health care-associated,” “healthcare associ-

ated,” and “healthcare associated OR health care-associated OR

health care associated OR healthcare-associated” gave a total

of 54,638 articles. The search terms “blood stream infection,

bloodstream infection, bacteremia,” “bloodstream infection,”

and “blood stream infection,” combined using the “OR” func-

tion, yielded a total of 27,839 articles. The search term “inef-

fective therapy OR ineffective antibiotic therapy OR delayed

antibiotic treatment OR delayed receipt of effective antimicro-

bial therapy OR inadequate antimicrobial treatment OR delay

in effective therapy” yielded a total of 24,230 articles. Com-

bining the “bloodstream infection…” search with the “ineffec-

tive therapy…” search, using the “AND” function, resulted in

a total of 232 articles. All these articles were reviewed; 13 were

relevant to the statement.

Evidence

Health care–associated status is a risk factor for ineffective an-

tibiotic therapy of BSI. One study specifically focused on the

impact of health care–associated status on the likelihood of in-

effective therapy for patients with BSI [75]. In this prospective,

multicenter, cohort study of 466 adults with BSI, only 132 (28%)

had community-acquired BSI. The most common pathogens in

BSI were E. coli (14.2%) and MRSA (13.1%). Although the mi-

crobiological characteristics of nosocomial and non-nosocomial

health care–associated BSIs were similar, microbiological char-

acteristics of both groups differed significantly from those of

community-associated BSI. In multivariable logistic regression

analysis, both health care–associated (OR, 3.1; 95% CI, 1.6–6.1)

and nosocomial (OR, 4.3; 95% CI, 2.2–8.3) status were inde-

pendently associated with ineffective initial antibiotic therapy.

Specific causes of BSI, including MRSA (OR, 1.7; 95% CI, 1.0–

2.8) and Enterococcus species (OR, 2.3; 95% CI, 1.3–4.1), were

also associated with ineffective initial therapy.

Assessment of association between appropriate antibiotic

therapy and mortality in patients with bacteremia. Studies

of the association between inappropriate therapy and mortality

among patients with bacteremia have yielded conflicting results.

One recent article [76] systematically reviewed the published

literature evaluating the association between inappropriate an-

tibiotic therapy and mortality among patients with bacteremia.

The authors found that 51 studies meeting their inclusion cri-

teria exhibited significant heterogeneity in design, definition,

measurement of variables, and statistics. Thirty-four studies

(67%) measured the severity of illness, but only 6 (12%) spec-

ified when it was assessed. Only 8 studies (16%) defined in-

appropriate antibiotic therapy as that which was inactive in

vitro against the isolated organism and was not consistent with

current clinical practice recommendations and also distin-

guished between empirical and definitive treatment. McGregor

et al. [76] identified key methodological recommendations to

improve the validity and generalizability of future studies, in-

cluding a robust, consistent definition of “inappropriate” ther-

apy based on in vitro susceptibility data; separate consideration

of empirical and definitive therapy; and appropriate statistical

adjustment for the baseline severity of illness of the patient.

Association between patient outcome and antibiotic therapy

for BSI caused by MDR gram-negative pathogens. A recent

meta-analysis of 16 peer-reviewed studies examined associa-

tions between ESBL production in Enterobacteriaceae species

causing bacteremia, time to effective antibiotic therapy, and

patient mortality [77]. Meta-analysis of crude RR demonstrated

a significantly increased incidence of delay in effective therapy

(pooled RR, 5.56; 95% CI, 2.94–10.51; ) and signifi-P ! .001

cantly increased mortality (pooled RR, 1.85; 95% CI, 1.39–2.47;

) in bacteremia caused by ESBL-producing bacteria.P ! .001

The meta-analysis was unable to evaluate adjusted mortality,

because only 1 of the 16 included studies reported these data.

A total of 7 additional reports were published after the en-

rollment period for the meta-analysis [78–84]. All were ret-

rospective, and all but 1 was a single-center study [80]. Most

[1, 5, 7, 10,78, 81, 82, 84] but not all [79, 83] of the 7 additional

studies found an association between delayed effective therapy

for BSI caused by MDR gram-negative pathogens and mortality.

Consistent with the report by McGregor et al. [76], significant

heterogeneity existed among the 7 studies in patient population,

definitions of delayed antibiotic therapy, follow-up period, and

statistical methodology. Moreover, establishing the risks of at-

tributable mortality remains difficult.

Using classification and regression tree (CART) analysis,

Lodise et al. [81] evaluated the relationship between delayed

appropriate antibiotic therapy and risk of 30-day mortality in

100 patients with nosocomial P. aeruginosa bacteremia. Delayed

antibiotic therapy was defined using CART analysis as receipt

of effective antibiotic therapy 152 h after the culture result was

obtained. Mortality was significantly higher among patients

with delayed appropriate antibiotic therapy than among pa-

tients whose therapy was not delayed (44% vs. 19%; P p



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). Appropriate antibiotic therapy delayed 152 h was in-.008

dependently associated with resistance to 13 antibiotic classes

(adjusted OR [AOR], 4.6; 95% CI, 1.9–11.2; ), chronicP p .001

obstructive pulmonary disease (AOR, 5.4; 95% CI, 1.5–19.7;

), and 30-day mortality (OR, 4.1; 95% CI, 1.2–13.9;P p .01

) among patients with P. aeruginosa BSI.P p .03

Tumbarello et al. [84] sought to identify the impact of in-

adequate initial antibiotic therapy (defined as initiation of treat-

ment with active antimicrobial agents 172 h after collection of

the first positive blood culture specimen) on 21-day mortality

in 186 hospitalized patients with BSI caused by ESBL-producing

organisms. Patients receiving inadequate treatment had a 3-fold

increase in mortality, compared with the group receiving ade-

quate treatment (59.5% vs. 18.5%; 95% CI, 1.76–3.22; ).P ! .001

In multivariate analysis, the significant predictors of mortality

were inadequate initial antimicrobial therapy (OR, 6.28; 95% CI,

3.18–12.42; ) and unidentified primary infection siteP ! .001

(OR, 2.69; 95% CI, 1.38–5.27; ). The antibiotic regimensP p .004

most frequently classified as inadequate were based on oxyimino

cephalosporin or fluoroquinolone therapy.

Using a multicenter, nested, case-control study, Hyle et al.

[80] evaluated the association of inadequate initial antimicro-

bial therapy with mortality in 187 patients with BSI caused by

ESBL-producing organisms. Initial antimicrobial therapy was

defined as inadequate when there was 148 h between the time

a culture specimen was obtained and the initiation of therapy

with an agent to which the infecting organism was susceptible.

Infection with MDR ESBL-producing E. coli or Klebsiella species

(AOR, 14.58; 95% CI, 1.91–111.36) and health care–acquired

infection with ESBL-producing E. coli or Klebsiella species

(AOR, 4.32; 95% CI, 1.49–12.54) were independent risk factors

for inadequate initial antimicrobial therapy, and inadequate

initial antimicrobial therapy was an independent risk factor for

mortality among patients with nonurinary infection with ESBL-

producing E. coli or Klebsiella species (AOR, 10.04; 95% CI,

1.90–52.96).

Anderson et al. [78] used multivariable logistic regression to

identify predictors of all-cause in-hospital mortality among 60

patients with bacteremia due to ceftazidime-resistant Klebsiella

pneumoniae. Only 72% of patients received effective therapy

within 5 days after the diagnosis of BSI. Delay in the initiation

of effective therapy for 172 h after diagnosis of BSI was an

independent predictor of mortality (OR, 3.32; 95% CI, 1.07–

10.3; ).P p .04

Micek et al. [82] evaluated 305 patients with P. aeruginosa

BSI to determine whether the administration of appropriate

initial antimicrobial treatment was associated with a better clin-

ical outcome and to examine the relationship between the em-

pirical administration of combination antimicrobial therapy for

gram-negative pathogens and appropriate treatment for P. aeru-

ginosa BSI [82]. In-hospital mortality was statistically greater

for patients receiving inappropriate initial antimicrobial treat-

ment than for patients receiving appropriate initial treatment

(30.7% vs. 17.8%; ). Multiple logistic regression anal-P p .018

ysis identified inappropriate initial antimicrobial treatment

(AOR, 2.04; 95% CI, 1.42–2.92; ) as an independentP p .048

predictor of in-hospital mortality. An appropriate initial anti-

microbial regimen was administered more often to patients

receiving empirical combination antimicrobial treatment for

gram-negative bacteria than to those receiving empirical mono-

therapy (79.4% vs. 65.5%; ).P p .011

Two studies found no increased risk with delayed effective

therapy for BSI caused by MDR gram-negative pathogens. Osih

et al. [83] assessed the effect of appropriate empirical therapy

on in-hospital mortality and length of stay among 167 patients

with P. aeruginosa BSI. Adequate empirical antibiotic therapy

was defined on the basis of in vitro susceptibility testing from

8 h before the first positive blood culture to the time the sus-

ceptibility results were known. After adjustment for age, severity

of illness, and time at risk, appropriate empirical antibiotic

therapy was not significantly associated with mortality (OR,

0.96; 95% CI, 0.31–2.9; ). Deal et al. [79] sought toP p .58

identify predictors of in-hospital mortality among 124 patients

with bacteremia caused by Enterobacter or Citrobacter species

from 1998 through 2004. Appropriate empirical antibiotic ther-

apy was administered to three-quarters of the patients and was

similar among survivors and nonsurvivors (74% vs. 81%;

). An important limitation to this investigation wasP p .51

sample size.

Association between patient outcome and antibiotic therapy

for MRSA bacteremia. Two meta-analyses involving 16000

staphylococcemic patients have shown that the mortality rate

among patients with MRSA bacteremia was significantly greater

than that among patients with MSSA bacteremia [85, 86]. Using

data from 13900 patients from 30 studies, Cosgrove et al. [85]

showed that mortality was significantly higher among patients

with MRSA bacteremia than among patients with MSSA bac-

teremia (36% vs. 23%; RR, 1.42; 95% CI, 1.25–1.63; ).P ! .001

Whitby et al. [86] reviewed 9 studies of nosocomial S. aureus

bacteremia published in 1990–2000. In this analysis, the RR of

death also was significantly higher among patients with MRSA

bacteremia (29% vs.12%; RR, 2.12; 95% CI, 1.76–2.57; P !

)..001

Several investigations have sought to quantify the impact of

delayed effective therapy on outcomes for patients with MRSA

bacteremia [87–90]. Results have varied, with 2 studies finding

no difference in mortality, and 2 studies finding higher mortality

rates among patients with MRSA bacteremia receiving delayed

antibiotic therapy. Roghmann et al. [90] retrospectively evaluated

132 episodes in 128 patients with MRSA bacteremia to estimate

the impact of delayed initiation of vancomycin on clinical out-

comes. Patients with MRSA bacteremia were significantly less



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likely to receive effective antibiotic therapy during the first 48 h

of hospitalization (45% vs. 98%; ) than were patients withP ! .01

MSSA bacteremia. However, this ineffective empirical therapy

was not significantly associated with an increased mortality risk

(RR, 0.82; 95% CI, 0.36–1.88) and did not change significantly

when adjusted for age, occurrence of sepsis, or nosocomial in-

fection. Kim et al. [88] evaluated 238 retrospectively identified

patients with MRSA bacteremia who received vancomycin or

ineffective therapy. Using a propensity-matching case-control de-

sign to adjust for confounding introduced by the clinician’s

choice of antibiotic, these investigators compared the outcomes

for patients with MRSA bacteremia who received inappropriate

empirical therapy with those of control patients with a similar

score but who received vancomycin. In the matched case-control

analysis of 50 propensity score–matched pairs with MRSA bac-

teremia, inappropriate empirical antibiotic therapy was not as-

sociated with a statistically significant difference in mortality (OR,

1.15; 95% CI, 0.51–2.64).

By contrast, 2 investigations found higher mortality among

patients receiving delayed effective therapy for S. aureus bac-

teremia. Using CART analysis, Lodise et al. [89] evaluated the

impact of delayed effective therapy on 167 retrospectively iden-

tified patients with nosocomial S. aureus bacteremia. The break-

point between delayed and early therapy by use of CART anal-

ysis was 44.75 h. In a multivariate analysis, delayed treatment

was found to be an independent predictor of infection-related

mortality (OR, 3.8; 95% CI, 1.3–11.0; ) and was as-P p .01

sociated with longer hospital stay when compared with early

treatment (20.2 vs. 14.3 days; ). The authors concludedP p .05

that delay of therapy has deleterious effects on clinical outcomes

and underscores the importance of early appropriate therapy.

Similar conclusions were reached by Khatib et al. [87], who

found that, in a cohort of 342 retrospectively identified patients

with S. aureus bacteremia, the time to effective antibiotic ther-

apy was longer for MRSA-infected patients than for MSSA-

infected patients (25.5 vs. 9.6 h; ) and all-cause mor-P ! .0005

tality was higher among patients receiving inappropriate

therapy than among those receiving appropriate therapy (35.0%

vs. 20.9%; ).P p .02

Association between patient outcome and antimicrobial

therapy for fungal BSI in patients with specific risk factors.

Two studies evaluated the risk of delayed effective therapy in

fungemic patients. Garey et al. [91] evaluated the relationship

between treatment delay and mortality in 230 retrospectively

identified patients with Candida BSI. Although the mortality

was the lowest among patients who began therapy on day 0

(15%), day 1 (24%), day 2 (37%), or day 3 or later (41%)

( for trend), only 40% of patients received antifungalP p .0009

therapy within the first day. By multivariate modeling, increased

time (per day) to administration of fluconazole was indepen-

dently associated with mortality (AOR, 1.5; 95% CI, 1.09–2.09;

). In the second study, Morrell et al. [92] evaluatedP p .0138

157 candidemic hospitalized patients to identify the influence

of delayed empirical antifungal treatment on clinical outcome.

By multivariable analysis, administration of antifungal treat-

ment 112 h after the first positive blood culture specimen was

drawn (AOR, 2.09; 95% CI, 1.53–2.84; ) was inde-P p .018

pendently associated with in-hospital mortality. Of note, only

5.7% of patients received antifungal therapy within 12 h after

the initial positive result of blood culture. Investigators in both

of these studies concluded that delay in initiation of fluconazole

therapy for hospitalized patients with candidemia had a sig-

nificant impact on mortality. Delayed treatment of Candida BSI

could be minimized by the development of more-rapid diag-

nostic techniques for the identification of Candida BSI or

through increased use of empirical antifungal treatment for

selected patients at risk for fungemia.

Grading of Evidence


members considered the nature of the evidence supporting this

statement to be category II (67% of votes) or category III (33%

of votes) (table 3).

Level of Support



73% voted to accept the statement with some reservations, and

18% voted to accept the statement with major reservations. In

comparison, of the 744 IDSA members who participated in the

online survey, 25% voted to accept the statement completely,


voted to accept the statement with major reservations, 17%

voted to reject the statement with reservations, and 4% voted

to reject the statement completely (figure 4).

Discussion

This statement is critically important, given the growing prob-

lems of sepsis, bacteremia [93], and antimicrobial resistance

[94]. The majority of the studies reviewed for this statement

support the assertion that delayed appropriate antibiotic ther-

apy is associated with higher mortality among patients with

BSIs. Although none of the studies were able to accurately

establish causal relationships between delayed appropriate an-

timicrobial therapy and increased mortality and most suffered

in one way or another from methodologic limitations [76],

their conclusions are generally consistent with current treat-

ment guidelines for other HAIs [1] and with previous reports

evaluating the impact of such treatment delays for patients with

sepsis [3]. As evidenced by the results of the IDSA membership

poll related to this statement, the important influence of time



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Figure 4. Voting comparison for statement 4 (“Health care–associated BSIs require empiric coverage for MDR gram-negative bacteria and MRSA,as well as coverage for fungal pathogens in patients with specific risk factors”). “IDSA” refers to the members of the Infectious Diseases Society ofAmerica who responded to a Web-based survey; “Summit” refers to the Health Care–Associated Infection Summit panel. BSI, bloodstream infection;MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcus aureus.

to administration of effective antimicrobial therapy on the clin-

ical outcome also makes intuitive sense to many clinicians.

The primary “rate-limiting steps” to effective antimicrobial

therapy for health care–associated BSI remain diagnostics and

susceptibility testing. Even when guided by local antimicrobial

susceptibility, empirical therapy often becomes little more than

an educated guess. Until diagnostic strategies emerge to provide

real-time, point-of-care information on the identification and

susceptibility of a bloodstream pathogen, clinicians will be

forced to make important decisions about initial antibiotic se-

lection without the luxury of definitive data. In this light, ob-

servations from these studies are important.

Among patients with BSI caused by gram-negative patho-

gens, early effective therapy was usually associated with reduced

mortality, and the likelihood of accomplishing early effective

therapy was higher when combination empirical antimicrobial

therapy was employed. Obviously, clinicians should consider

both the risks and benefits of adding a second antibiotic—often

an aminoglycoside—to an empirical regimen to treat gram-

negative pathogens in individual patients. However, the pre-

dominance of MRSA as a cause of health care–associated bac-

teremia, the availability of an FDA-approved agent for the

treatment of S. aureus bacteremia and right-sided endocarditis

(e.g., daptomycin), and the prospects of several anti-MRSA

agents in late stages of clinical development emphasize the need

for appropriately designed clinical studies to better address this

important issue. Significant controversy remains over the role

of vancomycin for treatment of MRSA bacteremia—whether

empirical or targeted [95, 96].

Finally, the emerging importance of fungi as a cause of BSI

and sepsis is a potentially important change to consider in the

management of BSI. For example, in an evaluation of the hos-

pital discharge records of 110 million cases of sepsis in the

United States over 22 years, there was an annualized increase

in the incidence of sepsis of 8.7%, from ∼164,000 cases (82.7

per 100,000 population) to nearly 660,000 cases (240.4 per

100,000 population). During this time, the rate of sepsis due

to fungal organisms increased by 207% [93]. Given the in-

creasing importance of fungemia and the suggestion that early

empirical antifungal therapy may reduce mortality among pa-

tients with this infection, further studies are clearly needed to

help determine which patients, if any, should receive empirical

antifungal treatment.

Future Directions

Future directions discussed by the summit members reflected

many of the limitations indicated by McGregor et al. [76].

Appropriately designed epidemiologic studies with rigorous at-

tention to important design details are required, including a

consistent definition of “inappropriate” therapy based on in

vitro susceptibility data, separate consideration of empirical and

definitive therapy, and appropriate statistical adjustment for the

baseline severity of illness of the patient. The need for more-

rapid diagnostic tests was emphasized. Finally, until such bed-

side diagnostic technologies are available, additional studies to

identify patients at risk for colonization or infection with MDR

pathogens—especially the fungi—are required to best balance

the dual needs for judicious and effective empirical antimicro-

bial therapy for patients with BSIs.

STATEMENT 5: INITIAL APPROPRIATEANTIMICROBIAL THERAPY AND SOURCECONTROL ARE THE MOST IMPORTANTDETERMINANTS OF OUTCOME IN SEVERESEPSIS AND SEPTIC SHOCK


Severe sepsis and septic shock are commonly encountered con-

sequences of severe infection, both community acquired and

hospital acquired [97]. Sepsis and its adverse sequelae, shock

and organ dysfunction, are currently the 10th leading cause of

death in the United States and one of the most common causes

of death in the noncoronary ICU [97, 98]. Martin et al. [93]

found that the incidence of sepsis in the United States has



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dramatically increased over a 22-year period (1979–2000), from

82.7 cases per 100,000 population to 240.4 cases per 100,000

population, for an annualized increase of 8.7%. The incidence

of severe sepsis is predicted to continue to rise in the next 2

decades [99].

To prevent the progression to organ dysfunction and other

adverse sequelae of severe sepsis and septic shock, it is impor-

tant to identify the patient with sepsis as early as possible and

to institute effective therapy [97, 98, 100]. Representatives from

11 societies proposed a consensus guideline for severe sepsis

and septic shock management [101], and they recommended

the following actions: the early administration of effective an-

tibiotics, source control when appropriate, provision of early

goal-directed fluid resuscitation and vasopressor support when

required, maintenance of adequate oxygenation and ventilation

as necessary, use of physiologic steroid-replacement therapy for

vasopressor-dependent patients with relative adrenal insuffi-

ciency, antithrombotic therapy when warranted and not con-

traindicated, and prevention of the various complications of

critical illness [101]. The Surviving Sepsis Campaign recently

published an update to these recommendations [102] that ad-

vises institution of early, effective antibiotic therapy; evaluation

of the need for source control; early, goal-directed fluid resus-

citation with either crystalloid or colloid norepinephrine or

dopamine as needed to maintain a mean arterial blood pressure

�65 mm Hg; dobutamine for patients with myocardial de-

pression; packed RBCs to treat hemoglobin levels of !7.0 g/dL;

use of lung-protective ventilatory support strategies when

needed; weaning from ventilatory support by protocol and

spontaneous breathing trials; prevention of complications of

critical illness (insulin to maintain blood sugar levels at !150

mg/dL); deep vein thrombosis prophylaxis; stress ulcer pro-

phylaxis; and use of sedation protocols [102].

The use of early, effective antibiotic therapy and source con-

trol, when indicated, has been considered the cornerstone of

sepsis therapy. Conventional wisdom would suggest that ap-

propriate (effective) antibiotic therapy is essential for an im-

proved outcome. This hypothesis will never be clinically tested

because it would be considered unethical to deprive a patient

of timely or effective antibiotic treatment.

Most of our current evidence in support of early, effective

antibiotic therapy is based on retrospective outcome analysis

comparing early, effective antibiotic therapy with initially in-

effective antibiotic agents. Because the definition of sepsis has

varied over time and, in the older literature, often required the

presence of bacteremia and hypotension, it is difficult to make

comparisons with some of the current data [103]. However, it

is still apparent that, regardless of the definition, mortality rates

improve with timely use of effective, appropriate antibiotic

therapy. Other important aspects of antibiotic effectiveness re-

late to the timing of antibiotic therapy (early vs. delayed ad-

ministration). Studies that are amenable to prospective, ran-

domized clinical trials involve the use of single versus multiple

antibiotic agents and the effects on outcome parameters.

The adequacy of source control is also a difficult topic to

evaluate with the published literature [104]. Few studies have

commented on the adequacy of drainage or debridement. The

adequacy of source control is evaluated primarily by retro-

spective review of the clinical course or by a post hoc adju-

dication committee. As in investigations evaluating the effec-

tiveness of antibiotic therapy, ethical concerns preclude a study

of adequate versus inadequate source control. Therefore, to

answer both of these important questions, we must turn our

attention to an analysis of the limited available literature, with

emphasis on clinical trials that have evaluated or commented

on the adequacy of either antibiotic therapy or source control,

as it relates to outcome for patients with sepsis.

Methods

A PubMed search to identify studies related to appropriate

antibiotic use and source control in sepsis outcome was per-

formed on 14 September 2007. The search was limited to 1996

through September 2007, and all searches were restricted to the

English language, adult humans, and full-text articles. The text

words “adequate antibiotics” yielded 18,240 articles, “sepsis/

septic shock” yielded 14,423 articles, and “survival/mortality”

yielded 93,638 articles. When the search for “adequate anti-

biotics” was combined with that for “sepsis/septic shock,” the

result was 1209 articles. The combination of the search for

“adequate antibiotics” and the search for “survival/mortality”

yielded 7744 articles. When the search was limited to “adequate

antibiotics AND sepsis/septic shock AND survival/mortality,”

the result was 680 articles. A review of the titles and abstracts

of the 680 articles resulted in 16 articles that were relevant to

the statement. In addition, an evidence-based review from the

Surviving Sepsis Campaign on the topics of adequate antimi-

crobial therapy and adequate source control was examined

along with the references from these articles [100, 104].

Evidence

To evaluate evidence concerning appropriate antibiotic therapy

for severe sepsis and septic shock, we must first acknowledge

that no clinician would intentionally give a patient ineffective

antibiotic therapy. It is convention to classify appropriate or

effective antibiotic therapy on the basis of the culture and sus-

ceptibility results; however, not all patients with sepsis will have

positive culture results. Most large clinical trials report that

approximately one-third of patients have positive blood culture

results and approximately one-quarter of patients will have no

positive culture result of any type [105]. It is also disappointing

to find that several large epidemiologic studies and clinical trials

involving patients with sepsis do not give any data concerning



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the administration of effective antibiotic therapy or the ade-

quacy of source control [106, 107]. Other important questions

(related to the use of culture and susceptibility results) surround

the ability of in vitro culture results to reflect in vivo effects of

antibiotics, as well as the debate about the thresholds differ-

entiating a true pathogen from a colonizing organism. A ret-

rospective review of 612 patients with bacteremia caused by

gram-negative bacteria demonstrated a significant reduction in

mortality when appropriate antibiotic therapy was administered

[108]. Fish [109] reviewed mortality differences between pa-

tients receiving appropriate antimicrobial therapy and patients

receiving inappropriate antimicrobial therapy in 11 studies and

demonstrated an association between a significant reduction in

mortality and appropriate antibiotic treatment.

Furthermore, in the Surviving Sepsis Campaign, the 11 so-

cieties used a modified Delphi method to define the role of

effective antimicrobial therapy in the management of severe sep-

sis and septic shock [100]. The consensus committee concluded

that prompt institution of effective antimicrobial therapy is one

of the most important predictors of outcome; unfortunately,

most of the evidence in support of their recommendations re-

flects category III, IV, or V evidence (table 3). Using the same

modified Delphi method to assess source control in the man-

agement of severe sepsis and septic shock, the same group con-

cluded that source control represents a key component for suc-

cessful sepsis management and should be used when indicated

[104]. Source control includes drainage of infected fluids, de-

bridement of infected soft tissues, and removal of infected devices

or foreign bodies. Source control should correct anatomic de-

rangements resulting in ongoing contamination and restore func-

tion [104].

In Spain, Garnacho-Montero et al. [110] conducted a pro-

spective cohort study of 406 critically ill patients with sepsis in

a tertiary care hospital, to determine the impact of effective,

empirical antibiotic therapy on early, 28-day, and 60-day mor-

tality. The administration of inadequate antibiotic therapy was

associated with an RR of 1.55 (95% CI, 1.20–2.02) for increased

mortality, compared with effective antibiotic therapy. An ob-

servational, prospective cohort study of 3413 patients with BSI

also demonstrated an increased mortality RR (1.6; 95% CI,

1.3–1.9) associated with the administration of inadequate an-

tibiotic therapy [111]. Ineffective antibiotic therapy was found

to increase all-cause mortality (52.1% vs. 23.5%; RR, 2.22; 95%

CI, 1.79–2.76; ) and infection-related mortality (42%P ! .001

vs. 17.7%; RR, 2.37; 95% CI, 1.83–3.08; ) in 2000 con-P ! .001

secutive ICU patients included in a prospective, observational,

cohort study [3]. In this study, the use of ineffective antibiotics

was greater in the setting of nosocomial infection with or with-

out prior antibiotic therapy. A prospective study of 707 patients

with bacteremia and/or fungemia evaluated the impact of ef-

fective versus ineffective antimicrobial therapy administered

initially, after results of cultures were obtained, and after the

susceptibility results were available; this study noted an increase

of up to 3.18 in the RR for death, when effective therapy was

compared with ineffective therapy at all time points [112].

The investigation of innovative therapies to improve the out-

come of severe sepsis and septic shock seems a perfect oppor-

tunity to evaluate the relationship between effective antibiotic

therapy and outcome. Unfortunately, this important variable

is often not assessed as part of a trial. Typically, the evaluation

of effective antibiotic and/or source control therapy involves

the use of a post hoc adjudication committee to evaluate the

culture and susceptibility results in relation to the antimicrobial

agents administered. A multicenter, prospective, randomized,

double-blind, controlled trial of high-dose intravenous im-

munoglobulin (IVIG), in addition to antibiotic therapy, given

to patients with sepsis undergoing surgery, found that overall

mortality increased from 20.4% with effective antibiotic therapy

to 87.5% with ineffective therapy [113].

In the PROWESS trial, drotrecogin alfa (activated) signifi-

cantly reduced mortality among patients with severe sepsis, but

148 patients (8.8%) in the intention-to-treat population (pa-

tients given drotrecogin alfa [activated], ; patients givenn p 74

placebo, ) received inadequate antibiotic therapy [114].n p 74

In a subsequent analysis, it was noted that the observed mor-

tality rates for patients given drotrecogin alfa (activated) and

patients given placebo who did not receive adequate antibiotic

therapy (29.7% and 43.2%, respectively) were higher the ob-

served mortality rates for those who received adequate anti-

infective therapy (24.2% and 29.6%, respectively) [115]. The

provision of adequate antimicrobial treatment, when evaluated,

has been quite variable, with reported values ranging from 75%

[116] to 88% [117].

The timing of antibiotic administration has also been found

to be an extremely important factor in outcome. A retrospective

cohort study of 2731 patients with hypotension and sepsis

found that mortality increased 7.6% for each 1-hour delay in

antibiotic administration after the onset of hypotension [4].

When antibiotics were administered within 30 min after the

onset of hypotension, the survival rate was 82.7%, but it fell

to 42% when the antibiotics were delayed 6 h after the onset

of hypotension. To improve the timely administration of an-

tibiotics and other diagnostic and therapeutic aspects of sepsis

management, clinicians have incorporated recommended ther-

apies into bundles of care [118]. Nguyen et al. [118] conducted

a 2-year, prospective, observational cohort study of 330 patients

who presented to the emergency department with severe sepsis

or septic shock, and they found a significant reduction (from

20.8% to 39.5%; ) in mortality when bundles were usedP ! .01

and, specifically, when antibiotics were administered within 4

h after presentation (OR, 0.38; 95% CI, 0.18–0.80; ).P p .03

Adequacy of source control is evaluated even less frequently



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than is antimicrobial therapy. Among patients requiring surgery

for source control in a multicenter, prospective, randomized,

double-blind, placebo-controlled trial of platelet-activating fac-

tor acetylhydrolase for treatment of severe sepsis and septic

shock, adequate source control occurred in 190% of both treat-

ment groups [117]. In contrast, in the PROWESS trial of dro-

trecogin alfa (activated) for severe sepsis, the initial source-

control procedure was judged to be adequate in only 90 (50.8%)

of 177 patients receiving drotrecogin alfa (activated) and 86

(47.3%) of 182 patients receiving placebo. Initial source control

was inadequate for 38 (21.5%) of 177 patients receiving dro-

trecogin alfa (activated) and 51 (28.0%) of 182 patients re-

ceiving placebo and was indeterminate for 49 (27.7%) and 45

(24.7%), respectively. In patients with adequate or inadequate

source control, no reduction in mortality was noted for dro-

trecogin alfa (activated). In patients with indeterminate source

control, drotecogin alfa (activated) was associated with a re-

duction in mortality (37.0% vs. 56.6%; OR, 0.65; 95% CI, 0.43–

1.00; absolute risk reduction, 19.6%) [119].

Grading of Evidence

On the basis of a review of the 12 studies cited above, 67% of

the workshop members agreed that the nature of the evidence

available to support this statement was category II, whereas

17% voted category III, and 17% voted category V (table 3).

Level of Support




voted to accept the statement with major reservations, and 0%

voted to reject the statement. In comparison, of the 744 IDSA






pletely (figure 5).

Discussion

Consideration of the statement concerning the importance of

effective antibiotics and source control in outcomes for patients

with severe sepsis and septic shock caused the vast majority

(180%) of the summit participants to support the statement

either completely or with some reservations. This conclusion

was reached by the participants despite the lack of multicenter,

prospective, randomized, placebo-controlled, double-blind

clinical trials substantiating the importance of effective anti-

biotic therapy in outcomes for patients with severe sepsis and

septic shock. Despite this lack of evidence, most clinicians be-

lieve that administration of early, effective antimicrobial therapy

and source control, when indicated, are among the key com-

ponents of management of severe sepsis and septic shock. Other

key components of effective sepsis management include fluid

resuscitation, restoration and maintenance of hemodynamic

function, support of oxygenation and ventilation as necessary,

and prevention of the complications of critical illness [97, 98,

101, 102]. Ethical considerations and common sense prohibit

conducting clinical trials to establish the key role for effective

antibiotics and source control in the management of severe

sepsis. It is also impossible to establish the relative value of one

key component compared with another. The various compo-

nents of effective sepsis management may be viewed as links

in a chain, and the chain is only as strong as its weakest link.

Therefore, without provision of all necessary aspects of sepsis

management, the outcome will be less than optimal.

Unfortunately, technology has not progressed to the point

where the clinician can rapidly diagnose the microbial cause

of the infection leading to sepsis or determine the susceptibility

of the organism at an early point in time and thus enable

provision of effective antibiotics at the time of diagnosis. Even

the diagnosis of sepsis is often not confirmed until the results

of cultures are available for review. This process typically takes

hours to days, and, to date, is not available during the “golden

hour” of initial management when the best outcome can be

expected [4]. The use of markers for sepsis (e.g., procalcitonin

levels, soluble triggering receptors expressed on myeloid cells,

and peptide nucleic acid fluorescence in situ hybridization) and

other techniques for early diagnosis may improve the diagnosis

of sepsis, but we still lack an early indicator of organism sus-

ceptibility to various antibiotics [120–122]. For now, clinicians

have directed their attention to the implementation of sepsis

bundles, to ensure the early administration of effective sepsis

therapy, including antibiotics, to achieve the best possible out-

comes for patients [118].

Future Directions

Although not necessarily the major determinant of outcome in

severe sepsis and septic shock, early, effective antibiotic therapy

and source control, when indicated, are among the key com-

ponents necessary for optimal outcome. Future efforts will

likely focus on uses of advanced diagnostic techniques to iden-

tify specific bacterial and fungal pathogens, such as fluorescence

in situ hybridization and PCR. These tests will help facilitate

early diagnosis of sepsis and will direct more-appropriate early

therapy. In addition, the efficacy of antibiotic treatment should

be more definitively investigated in terms of the MIC of the

microbe and the blood level and, potentially, the mechanism

of action of the antibiotic. Relying only on the categories “sus-

ceptible” or “resistant” may not adequately define “appropri-

ate” antibiotic treatment. This has particular relevance to an-

tibiotics such as vancomycin and aminoglycosides. This strategy



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Figure 5. Voting comparison for statement 5 (“Initial appropriate antimicrobial therapy and source control are the most important determinants ofoutcome in severe sepsis and septic shock”). “IDSA” refers to the members of the Infectious Diseases Society of America who responded to a Web-based survey; “Summit” refers to the Health Care–Associated Infection Summit panel.

not only will result in better sepsis outcome but also will assist

with antibiotic stewardship and potentially minimize the de-

velopment of bacterial resistance.

STATEMENT 6: VANCOMYCIN IS OBSOLETEFOR TREATING MRSA INFECTIONS


Vancomycin has been the workhorse antimicrobial for the treat-

ment of MRSA infections for 140 years. In the past decade,

the prevalence of hospital-associated MRSA infections has

reached 64% in most US hospitals [123]. In addition, there has

been a virtual explosion of community-onset MRSA infections

among young, healthy individuals in a wide variety of situa-

tions, including high school, college, and professional football

teams; prisons; and so forth. Although vancomycin was pre-

scribed sporadically and infrequently 20–30 years ago, its use

has increased exponentially over the past decade. As a conse-

quence, there is increasing evidence that vancomycin is not

currently as effective as it once was; this evidence results from

frank treatment failures as well as growing concern related to

the emergence of various types of vancomycin resistance. The

current epidemics of hospital-associated MRSA and commu-

nity-onset MRSA infections have developed rapidly, and there

are no concrete guidelines addressing the current problems

associated with treatment of MRSA infections. The purpose of

the current investigation is to examine the mounting evidence

regarding treatment failures and reduced in vitro activity of

vancomycin against MRSA.

Methods

A PubMed database search to identify studies related to van-

comycin was concluded on 26 September 2007. The search term

“vancomycin” yielded 13,064 articles. “Vancomycin” limited to

the English language resulted in 11,528 articles and, when com-

bined with “last ten years,” yielded 4181 articles. When these

elements were combined with “human,” 3166 articles were

found. Further narrowing of the field was accomplished by

combining the elements “failure” (162 articles), “Staphylococcus

aureus” (74 articles), and “MRSA” (30 articles). Excluding case

reports yielded 10 articles. Finally, 3 abstracts on in vitro sus-

ceptibility were added from abstracts from the annual meetings

of the IDSA and the Interscience Conference on Antimicrobial

Agents and Chemotherapy.

Evidence

Changes in the susceptibility of MRSA to vancomycin.

There have been 3 studies performed in the United States that

evaluated the in vitro susceptibility of MRSA strains to van-

comycin over time, with the objective of identifying trends in

the susceptibility of MRSA to vancomycin. In the first study,

the MIC90 values for vancomycin among MRSA strains were

compared in vitro at M. D. Anderson Hospital across a 20-

year period; 25 strains from 1985 and 28 strains from 2004

were examined. This study demonstrated that the MIC90 in-

creased from 0.2 mg/mL to 2.0 mg/mL during this nearly 20-

year time span [124]. The second study compared the in vitro

susceptibility of blood isolates of MRSA in 2002 with that of

blood isolates of MRSA in 2005 at the New England Medical

Center (Boston, MA) and demonstrated a dramatic increase in

the MICs for vancomycin (figure 6) [125]. The third study was

an in vitro investigation of MICs for vancomycin among 945

strains of S. aureus from 2000 and 1418 strains of S. aureus

from 2004. In 2000, 79.9% of strains had vancomycin MICs

of �0.5 mg/mL, and 19.9% ( ) had vancomycin MICs ofP ! .01

1.0 mg/mL. In contrast, in 2004, 28.8% had vancomycin MICs

of �0.5 mg/mL, whereas 70.4% ( ) had vancomycin MICsP ! .01

of 1.0 mg/mL [126]. According to this study, a marked increase

in vancomycin MICs was apparent for MRSA isolates in Los

Angeles from 2000 through 2004.

Clinical failure of vancomycin in patients with bacteremia

caused by MRSA strains with MICs of 4 mg/mL. An obser-

vational series of 14 case reports of clinical failures of vanco-

mycin for treatment of bacteremia caused by MRSA strains

with MICs of vancomycin 4 mg/mL were compiled [127]. These



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Figure 6. In vitro comparison of vancomycin MICs at the New EnglandMedical Center (Boston, MA), in 2002 and 2005. Adapted from [125].

Figure 7. Clinical failures of vancomycin treatment for vancomycin-susceptible Staphylococcus aureus: the role of MICs. Data are from [134].

failures were the primary evidence compelling the Clinical and

Laboratory Standards Institute to lower the vancomycin-sus-

ceptible MRSA MIC breakpoint to 2 mg/mL.

Vancomycin-resistant MRSA. Absolute resistance of

MRSA strains has been described [128]. These strains are called

“vancomycin-resistant MRSA” and have been defined as strains

with MIC of 116 mg/mL for vancomycin. Thus far, 7 vanco-

mycin-resistant MRSA strains have been described in Japan and

the United States [129].

Vancomycin-intermediate MRSA (VISA) and heteroresis-

tant VISA (hVISA). The first descriptions of emergence of

vancomycin-intermediate strains of MRSA [130] or glycopep-

tide-intermediate S. aureus [131] were from Japan, and these

are defined as having MICs of 4–8 mg/mL [130]. Soon there-

after, clinical failures of vancomycin for patients with MRSA

bacteremia caused by vancomycin-intermediate strains were re-

ported. In a retrospective study in Australia, 76% of 25 patients

with MRSA bacteremia who were given treatment with van-

comycin experienced failed therapy, as defined as persistence

of bacteremia for 17 days. Interestingly, these MRSA strains

were relatively susceptible to vancomycin, with MICs of 2–4

mg/mL [132]. Although these strains were defined as being VISA

strains, they contained populations of microbes that were re-

sistant to vancomycin. Because of the heterogenous population

of MRSA, these strains are called “hVISA.” In the laboratory,

demonstration of heteroresistance requires a large inoculum of

107 MRSA organims per mL because ∼1 in 100,000 bacteria is,

in fact, resistant to vancomycin. It likely has clinical relevance

for cases in which the “load” of MRSA is high, as one might

expect in a large abscess, necrotizing fasciitis, consolidative

pneumonia, bacteremia, and endocarditis. Because most clinical

laboratories are standardized to use inocula of 105 MRSA or-

ganisms for susceptibility testing, newer methods must be de-

veloped to alert clinicians of this phenomenon.

Failure of vancomycin in bacteremia caused by hVISA.

A retrospective study of isolates from all patients with MRSA

bacteremia ( ) in a hospital in Australia evaluated a 12-n p 53

month period (July 2001–June 2002), with the objective of

identifying the prevalence of hVISA and the outcomes for these

patients given treatment with vancomycin [133]. No VISA iso-

lates were recovered; however, 5 (9.4%) of 53 MRSA isolates

were heteroresistant to vancomycin. Patients infected with

hVISA were more likely to have high bacterial loads (P p

), compared with patients infected with vancomycin-sus-.001

ceptible MRSA, and patients with hVISA infections were more

likely to experience a failure of vancomycin treatment (P !

), compared with patients infected with vancomycin-sus-.001

ceptible MRSA [133].

Failure rate of vancomycin treatment as a function of rising

MICs in patients with infection caused by vancomycin-sus-

ceptible MRSA. A total of 122 S. aureus isolates, 63 of which

were MRSA with vancomycin MICs of 0.5–2.0 mg/mL, from

87 patients given treatment with vancomycin were analyzed.

Of the 87 patients, 45 had no clinical or bacteriological response

to vancomycin. Among the 36 clinically evaluable patients in-

fected with S. aureus strains that had the accessory gene

regulator (agr) group II polymorphism, 31 had an infection

that failed to respond to vancomycin, whereas only 5 had an

infection that responded successfully to vancomycin. There was

a significant association between vancomycin treatment failure

(45 of 63) and MIC increase ( ) (figure 7) [134].P p .004

Failure of vancomycin as a function of the rapidity of bac-

terial killing. This investigation analyzed isolates ( )n p 30

from patients with bacteremia in 24 US hospitals, with the ob-

jective of correlating clinical failure with in vitro vancomycin

susceptibility and bactericidal activity. For MRSA isolates with

vancomycin MICs �0.5 mg/mL, vancomycin was 55.6% suc-

cessful in the treatment of bacteremia, whereas vancomycin was

only 9.5% ( ) effective in cases in which MRSA MICs forP p .02

vancomycin were 1–2 mg/mL. In addition, the failure rate for

vancomycin was 100% if !4.71 log of bacteria were killed in 72

h ( ); 77% if 4.71–6.26 log of bacteria were killed in 72 hn p 9

( ); and 50% if 16.27 log of bacteria were killed in a 24-n p 13



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h period ( ). The differences between treatment groups weren p 8

statistically significant ( ) [135].P p .05

Vancomycin tolerance among MRSA isolates. Another

cause of failure of antimicrobial treatment is the phenomenon

of bacterial tolerance, which is defined as a minimum bacte-

ricidal concentration (MBC)/MIC ratio of �32 or an MBC of

�16. Of 207 evaluated strains of S. aureus, 102 were MRSA;

14.7% of wild-type MRSA demonstrated tolerance, whereas

69.3% of hVISA and 100% of VISA isolates demonstrated tol-

erance. Thus, even large doses of vancomycin may not reach

bactericidal blood and tissue levels sufficient to kill tolerant

strains of MRSA [136].

Does increasing the dose of vancomycin to achieve serum

trough levels of 115 mg/mL increase efficacy, or does it increase

nephrotoxicity? The rationale for this study was a perceived

increase in vancomycin treatment failures for infections caused

by vancomycin-susceptible MRSA strains with high MICs and

the general practice to recommend a higher vancomycin target

trough level of 15–20 mg/mL, in an effort to increase efficacy.

However, there are no data regarding potentially increased renal

toxicity associated with these higher doses.

In a prospective cohort study of patients with MRSA infec-

tions ( ), investigators sought to correlate the distribu-n p 95

tion of vancomycin MICs and treatment outcomes with trough

levels at least 4 times the MIC. There was no nephrotoxicity

when trough levels were !15 mg/mL. However, 11 (12%) of 63

patients developed nephrotoxicity with trough levels �15 mg/

mL. Multivariate analysis implicated concomitant nephrotox-

ins, such as aminoglycosides and amphotericin B. In the high-

trough-level group, only 2% (in the absence of nephrotoxins)

developed nephrotoxicity [137]. Of the 95 patients in the study,

51 (54%) were infected with high-MIC strains and had pneu-

monia (77%) and/or bacteremia. An initial response rate of

74% was achieved when the target trough level was attained,

irrespective of MIC. However, despite achieving the target

trough level, the group infected with high-MIC strains had

fewer end-of-treatment responses (24 [62%] of 39 vs. 34 [85%]

of 40; ) and higher infection-related mortality (11P p .02

[24%] of 51 vs. 4 [10%] of 44; ), compared with theP p .16

group infected with low-MIC strains. Infection with a high-

MIC strain ( ) and high APACHE II score ( )P p .03 P p .009

were independent predictors of poor response in multivariate

analysis. Nephrotoxicity occurred only in the high-trough-level

group (11 [12%] of 63); this was significantly predicted by

concomitant therapy with other nephrotoxic agents.

A high prevalence of clinical MRSA strains with elevated

vancomycin MICs (2 mg/mL) requires aggressive empirical van-

comycin dosing to achieve a trough level of 115 mg/mL. The

rationale for this recommendation is obvious, yet there is little

clinical experience with high vancomycin dosages, and toxicity

becomes an important issue, as discussed below. Combination

or alternative therapy should be considered for invasive infec-

tions caused by these strains.

Will higher trough levels of vancomycin be associated with

a higher incidence of renal toxicity? In a prospective review

of patients with HAP, 43 patients were followed up for changes

in creatinine clearance ( ). Overall, there was a 25% de-n p 43

crease in creatinine clearance among all patients receiving van-

comycin. There was a 30% decrease in creatinine clearance

among patients with a low trough level (5–15 mg/mL), com-

pared with a 60% decrease in creatinine clearance among pa-

tients with high trough levels of 115 mg/mL ( ) [65].P p .006

Grading of Evidence

Of the workshop participants, 83% voted that the evidence to

support the statement was category III, and 17% voted that it

was category II (table 3).

Level of Support

Interestingly, 36% of the summit participants voted to accept

the statement with some reservations, 36% voted to accept the

statement with major reservations, 18% voted to reject the

statement with reservations, and 9% voted to reject the state-

ment completely. In comparison, of the 744 IDSA members

who participated in the online survey, 1% accepted the state-

ment completely, 9% accepted the statement with some res-

ervations, 7% accepted the statement with major reservations,

38% rejected the statement with reservations, and 45% rejected

the statement completely (figure 8).

Discussion

This statement is of key importance, given the emerging data

regarding reduced susceptibility of MRSA to vancomycin and

the increasing reports of failure of vancomycin in the treatment

of clinical infections. Recognition of this problem is not yet

widespread, as evidenced by the IDSA membership’s diverse

responses to this statement that vancomycin is obsolete in the

treatment of MRSA infections. Summit participants’ responses

were diverse yet more accepting of the statement.

The quality of the evidence supporting emerging resistance

to vancomycin and so-called MIC creep is not robust, largely

because it reflects regional differences and is not yet on a na-

tional scale. Still, these small studies are compelling because

the studies were done in several different geographical regions

by independent investigators. There may be some bias, since

many of the sites are large hospitals in densely populated

regions of the United States where vancomycin use may be

greater. In addition, some studies are retrospective and start

with patients who experienced failure of vancomycin treatment.

Not surprisingly, some of the isolates from these cases have

reduced susceptibility to vancomycin. Still, all studies presented

here support the contention that strains of MRSA are emerging



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over time with reduced susceptibility to vancomycin and that

this phenomenon is associated with or causes treatment failures.

Thus, although the quality and size of these studies are not

robust, it is clear that vancomycin susceptibility among MRSA

isolates is changing rapidly, and these preliminary studies are

providing early warning of larger problems to come. It is also

true that very large doses of vancomycin may be necessary to

achieve an area under the concentration-time curve/MIC ratio

for MRSA infections caused by strains with vancomycin MICs

of 1–2 mg/mL [138].

Future Directions

Future directions discussed by the summit members clearly

involve additional studies. Prospective studies that evaluate the

in vitro susceptibility of MRSA strains to vancomycin on re-

gional and national scales are sorely needed. New assays to

detect heteroresistance among clinical isolates of MRSA need

to be developed and correlated with clinical outcomes. Finally,

prospective studies that evaluate clinical responses of MRSA

infections, in terms of susceptibility issues and vancomycin

trough levels, should be done immediately. Until then, if van-

comycin is to be used, these data mandate increased knowledge

of the MICs and vancomycin trough levels, to ensure that pa-

tients are given appropriate treatment. Specifically, clinical lab-

oratories need to provide clinicians with the actual vancomycin

MIC of the MRSA strain, because clinical failure increases pro-

portionally to the MIC, even among “susceptible” strains.

STATEMENT 7: SERIOUS HAIs DUE TOSUSPECTED GRAM-NEGATIVE BACTERIASHOULD BE TREATED EMPIRICALLY WITHDUAL COVERAGE THAT INCLUDES ANAMINOGLYCOSIDE


The terminology of HAIs is rapidly permeating the classification

of various infection types. Classification schemes for both BSIs

and pneumonia have already been adopted. These classifica-

tions identify specific patients at risk, as well as treatment rec-

ommendations. “HAIs” can describe a wide variety of infection

types; therefore, it is important to focus recommendations on

the basis of patient-specific circumstances. The evaluation of

this statement was insupportable in its entirety; therefore, the

review of the literature centered on the use of dual empirical

coverage as well as the use of an aminoglycoside in combination

therapy. The use of dual empirical coverage is well supported

in the literature; however, the selection of an aminoglycoside

is problematic because it is not necessarily appropriate in all

clinical situations. There are 5 inherent issues that will be ad-

dressed in the evaluation of this statement: the role of adequate

empirical therapy for serious HAI in the determination of out-

come [139], the potential value of combination antimicrobial

therapy in the determination of outcome [140], the potential

efficacy of aminoglycosides as a component of combination

antimicrobial therapy for serious HAI [3], the potential efficacy

of quinolones as a component of combination therapy for se-

rious HAI [141], and the influence of antibiotic-resistance sur-

veillance on selection of therapeutic agents [46]. Each of these

issues will be discussed with respect to evidence in favor of or

against acceptance of the statement.

Methods

A PubMed literature search was conducted on 4 September

2007 to identify studies related to dual empirical coverage of

infections with gram-negative pathogens. The search term

“cross infection/drug therapy or cross infection therapy” was

combined using the “AND” function with “antibiotic therapy

and gram-negative.” Results were limited to the English lan-

guage and studies published within the past 5 years. The search

yielded 204 articles, 2 of which were relevant to the statement.

A second PubMed search was conducted using the search terms

“gram-negative bacterial infections/drug therapy” and “cross

infection,” combined using the “AND” function. This search

yielded 200 articles, 10 of which were relevant to the statement.

Twelve additional articles were also reviewed from previous

searches.

Evidence

The role of adequate empirical therapy for serious HAI in the

determination of outcome. The outcome of serious HAI is

improved by selection of adequate empirical antibiotic therapy,

as defined by susceptibility of the infecting organism(s) to the

agent(s) selected. Several retrospective and prospective clinical

studies since the mid-1990s have provided statistical evidence

of the positive effect of adequate empirical antibiotic therapy

on clinical outcome. These studies have also concluded that

adjustment of therapy when susceptibility data become avail-

able does not reverse the unfavorable effect of inadequate em-

pirical therapy.

In 1997, Luna et al. [139] described a prospective cohort

study of 132 patients with VAP to determine the impact on

outcome of a change in antibiotic therapy based on the results

of culture of specimens collected by early bronchoalveolar lav-

age (BAL). Among patients from whom a pathogen was re-

covered by BAL, mortality was 91% after inadequate initial

therapy and 38% after adequate initial therapy ( ). WhenP ! .001

therapy was changed according to BAL culture results, mortality

was comparable to that among patients who continued to re-

ceive inadequate therapy. Kollef and Ward [140] reported the

results of a similar study in 1998 to determine the influence

of mini-BAL cultures on subsequent changes in antibiotic ther-

apy and outcomes in 130 patients with suspected VAP. Mortality

among patients for whom therapy was either begun or changed



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Figure 8. Voting comparison for statement 6 (“Vancomycin is obsolete for treating MRSA infections”). “IDSA” refers to the members of the InfectiousDiseases Society of America who responded to a Web-based survey; “Summit” refers to the Health Care–Associated Infection Summit panel. MRSA,methicillin-resistant Staphylococcus aureus.

at the time of BAL culture results was 60.8%, compared with

33.3% among patients requiring no change in initial antibiotic

therapy ( ). Thus, a delay in initiation of adequate ther-P ! .001

apy was associated with greater mortality.

A prospective cohort study by Kollef et al. [3] was subse-

quently reported in 1999; the report described 655 critically ill

infected patients admitted to the ICU. The overall mortality

was 15.6%. Mortality among patients receiving inadequate ini-

tial antimicrobial treatment was 52.1%, compared with 12.2%

among patients who received adequate initial treatment (P !

). The effects of inappropriate initial antimicrobial therapy.001

on outcomes for 286 patients with bacteremia due to antibiotic-

resistant organisms were reported by Kang et al. in 2005 [141].

In a study of patients with a high-risk source of bacteremia,

inappropriate initial antibiotic therapy was independently as-

sociated with increased mortality (mortality among those given

appropriate therapy, 27.4%; mortality among those given in-

appropriate therapy, 38.4%; ) (OR, 3.64; 95% CI,P p .049

1.13–11.72; ). Fraser et al. [46] reported similar resultsP p .030

in a study published in 2006 involving 920 patients with mi-

crobiologically documented infections. Thirty-day all-cause

mortality was 20.1% among those who received inappropriate

initial empirical antibiotic therapy and was 11.8% among those

who received appropriate therapy ( ). In a study ofP p .001

patients with bacteremia published in 2007 by Tumbarello et

al. [84], 186 patients infected with ESBL-producing organisms

had 21-day mortality of 59% after inadequate initial antimi-

crobial therapy, compared with 18.5% among those who re-

ceived adequate initial therapy ( ).P ! .001

The potential value of combination antimicrobial therapy

in the determination of outcome. The potential benefit of

combination antibiotic therapy, compared with effective single-

drug therapy, remains ill defined. However, in a retrospective

study of 115 patients with P. aeruginosa bacteremia, Chamot

et al. [142] found that adequate empirical combination therapy

yielded lower 30-day mortality than did adequate empirical

monotherapy, inadequate empirical monotherapy, or inade-

quate empirical combination therapy. In addition, adequate

definitive combination therapy given when susceptibility results

became available did not improve survival, compared with ad-

equate definitive monotherapy. These results support the ben-

efit of adequate empirical monotherapy or combination ther-

apy, compared with delayed definitive therapy for bacteremia

due to P. aeruginosa. Adequate combination empirical therapy

was also more effective than adequate empirical monotherapy.

Neutropenic patients accounted for 30% (34 of 115 patients)

of the study population.

A prospective, observational study of 230 patients with Kleb-

siella bacteremia showed no difference (20% vs. 18%; )P 1 .05

in 14-day mortality between those given monotherapy and

those given combination therapy (b-lactam plus aminoglyco-

side) [143]. However, for the subgroup of patients who ex-

perienced hypotension (systolic blood pressure, �90 mm Hg)

within 72 h before or on the day of the positive blood culture,

those who received combination therapy experienced signifi-

cantly lower mortality (24%) than did those who received

monotherapy (50%).

A meta-analysis published in 2004 reviewed 17 studies that

compared combination therapy and monotherapy for bacter-

emia caused by gram-negative organisms [144]. The authors

found no mortality benefit with combination therapy. However,

analysis of only P. aeruginosa bacteremia showed a significant

mortality benefit (OR, 0.50; 95% CI, 0.30–0.79).

In the above-mentioned studies, most of the effective com-

bination therapies used b-lactam and aminoglycoside agents to

which common isolates were susceptible. In the more recent

era of MDR gram-negative bacilli, use of novel empirical an-

tibiotic combinations may be dictated by advanced local resis-

tance patterns. In certain areas of New York City and Morocco,

effective empirical combination therapy requires use of a poly-

myxin alone or in combination with other agents, according

to special in vitro susceptibility tests [145–147].

The potential efficacy of aminoglycosides as a component

of combination antimicrobial therapy for serious HAIs.



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The potential efficacy of aminoglycosides as a component of

combination antibacterial therapy is illustrated by the studies

described above. Guidelines for the management of HAP, VAP,

and HCAP in adults were published jointly by the ATS and the

IDSA in 2005 [1]. Suggested antibiotic combinations included

either an aminoglycoside or quinolone, chosen on the basis of

local susceptibility data. Early evidence that aminoglycoside

therapy for serious pneumonia caused by gram-negative path-

ogens is relatively ineffective because of poor tissue penetration

is contradicted by more-recent pharmacokinetic/pharmaco-

dynamic studies indicating that optimal aminoglycoside ther-

apy is achieved by once-daily administration, not divided daily

doses [148].

The potential efficacy of quinolones as a component of com-

bination therapy for serious HAIs. The potential efficacy of

quinolones as a component of adequate empirical combination

therapy depends on the intensity of local use and likely the

degree of resistance among invading gram-negative pathogens.

A surveillance study published by Neuhauser et al. [149] ex-

amined fluoroquinolone resistance in 1994–2000. They found

that overall susceptibility to ciprofloxacin decreased from 86%

in 1994 to 76% in 2000 and was significantly associated with

increased use of fluoroquinolones. Other studies published dur-

ing the past decade have documented the rising use of fluo-

roquinolones in various areas of the United States and its as-

sociation with increasing resistance among gram-negative

bacilli [149–151].

The influence of antibiotic resistance surveillance on selec-

tion of therapeutic agents. Increasing antibiotic resistance

among gram-negative bacilli in the United States and inter-

nationally has been well documented in the past few decades.

Its local incidence should influence the selection of empirical

therapy for serious infections with gram-negative bacilli. Na-

tional surveillance studies in the United States have indicated

a greater degree of quinolone resistance than aminoglycoside

resistance among P. aeruginosa and Acinetobacter isolates, par-

ticularly from ICUs [152–154]. Routine colonization surveil-

lance in an ICU has demonstrated that knowledge of coloni-

zation status before infection is associated with higher rates of

appropriate therapy for patients with bacteremia caused by an-

tibiotic-resistant gram-negative bacilli [155]. A retrospective co-

hort study notes the clinical implications of resistance and the

value of accurate susceptibility information. In that study, Tam

et al. [156] examined 34 bacteremia episodes involving P. aeru-

ginosa isolates with reduced susceptibility to piperacillin-ta-

zobactam, which was given empirically for 7 episodes. Thirty-

day mortality was found to be 85.7% in the group receiving

piperacillin-tazobactam, compared with 22.2% in the group

receiving other antipseudomonal agents ( ). Tam et al.P p .004

[156] observed an increase in mortality among patients infected

with an isolate that had increased resistance, despite the fact

that these patients had received appropriate therapy. Currently,

there is no real clinical data supporting a synergistic effect of

dual coverage for P. aeruginosa or any other gram-negative

bacilli. The same is true for resistance. The main rationale for

dual coverage of gram-negative bacilli is to increase the like-

lihood of the administration of appropriate therapy. On another

note, in 2007, Livermore and Pearson [157] analyzed the utility

of international, national, and local resistance surveys. They

concisely summarized the essence of their findings in the title

“Antibiotic resistance: location, location, location,” emphasiz-

ing that “for patient management, good local data are essential”

[157, p. 7]. They highlighted the complexity of issues and large

variances in resistance rates according to country, patient char-

acteristics, and unit of care (i.e., nursing home vs. ICU). The

authors concluded that, although these surveys help to illustrate

trends, local susceptibility data are essential to good clinical

management.

Grading of Evidence


workshop members voted that the evidence to support the

statement was category II, 50% voted that it was category III,

and 17% voted that it was category V (table 3).

Level of Support

Overall, 27% of the workshop members voted to accept the

statement with some reservations, 64% voted to accept the

statement with major reservations, and 9% voted to reject the

statement with reservations. None of the summit members

voted to accept or reject the statement completely. In com-

parison, of the 744 IDSA members who participated in the

online survey, 30% voted to accept the statement completely,


voted to accept the statement with major reservations, 18%

voted to reject the statement with reservations, and 3% voted

to reject the statement completely (figure 9).

Discussion and Future Directions

In conclusion, this statement can be supported by evidence that

microbiologically adequate empirical treatment of serious HAIs

due to gram-negative bacteria provides optimal clinical out-

come. Evidence also supports the use of dual therapy to provide

broad empirical coverage, as well as improved mortality for

patients with bacteremia caused by P. aeruginosa. National sur-

veillance data from the United States provide evidence that

aminoglycosides retain greater susceptibility than do quino-

lones as potential second agents in combination therapy. How-

ever, in selected and expanding geographic areas, antimicrobial

resistance has progressed to include all aminoglycosides and

quinolones, as well as all b-lactams. This phenomenon pre-

cludes the use of a definitive general statement that includes a



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Figure 9. Voting comparison for statement 7 (“Serious HAIs due to suspected gram-negative bacteria should be treated empirically with dualcoverage that includes an aminoglycoside”). “IDSA” refers to the members of the Infectious Diseases Society of America who responded to a Web-based survey; “Summit” refers to the Health Care–Associated Infection (HAI) Summit panel.

single agent or class of agents as appropriate therapy in all

locations.

STATEMENT 8: PATIENTS WITH SERIOUS HAIsWHO HAVE RISK FACTORS FOR FUNGALINFECTIONS REQUIRE EARLY EMPIRICANTIFUNGAL THERAPY TO REDUCEMORTALITY


Traditionally, patients presenting to the hospital with suspected

BSI or severe sepsis have been considered at risk for infections

with selected pathogens, including MSSA, Streptococcus pneu-

moniae, and gram-negative organisms such as E. coli. Recog-

nition that risk factors for infection with antibiotic-resistant

pathogens include factors beyond the hospital setting has led

to the evolution of the concept of HAIs. Briefly, this concept—

explained in detail elsewhere in this supplement—attempts to

capture the fact that many patients regularly interact with the

health care system and are routinely exposed to extensive an-

timicrobial therapy outside the hospital. As such, they may

become infected with a broad range of pathogens, including

organisms traditionally classified as “community associated”

illness or with bacteria previously thought to arise only in hos-

pitalized persons who develop nosocomial syndromes.

One class of nonbacterial organisms has recently emerged as

an important pathogen causing nosocomial BSIs [158, 159].

Yeast represents an increasingly common cause of serious hos-

pital-acquired BSI. More specifically, Candida species are the

third or fourth most common cause of hospital-acquired BSIs,

depending on the epidemiologic literature reviewed [158, 159].

This observation begs the question as to whether this finding

applies to patients with health care–associated BSI. In other

words, does yeast now cause BSI in persons presenting to the

emergency department with a syndrome that resembles BSI or

severe sepsis? To validate the proposed statement, it is necessary

to explore 3 specific issues: What is the prevalence of Candida

as a cause of BSI in patients presenting to the emergency de-

partment? Does failure to treat candidemia result in adverse

outcomes for patients? Do patients with such candidal BSI have

risk factors for HAI?

Methods

A literature search of the PubMed database was conducted on

4 September 2007. The search was not limited to the English

language. The purpose of the search was to identify articles

addressing the epidemiology of candidemia, the distribution of

the specific species of Candida that may cause BSI, the prev-

alence of candidemia among patients presenting to the emer-

gency department, and treatment strategies for candidemia.

Specific search terms used included “Candida,” “candidemia,”

“fungus,” “fungemia,” “bloodstream infection,” and “sepsis.”

The term “candidemia OR fungemia” resulted in the identi-

fication of 2689 articles. Although searching for the terms

“healthcare associated” and “healthcare-associated” resulted in

150,000 potential articles, the combination of either of these

phrases with “candidemia OR fungemia OR BSI” yielded only

12 publications. To expand the potential number of studies to

be reviewed, the search strategy was subsequently modified to

incorporate these phrases: “inappropriate therapy,” “risk fac-

tors,” and “presumptive therapy.” These selections were pooled

in a Boolean fashion with the original search terms attempting

to capture BSI infection with yeast. Despite broadening the

search, only 4 additional articles potentially relevant to the

statement were located.

The paucity of published literature suggests that the concept

of health care–associated candidemia has not been well studied.

This may reflect that either the concept is relatively new or this

condition is not of clinical concern. In either case, the limited

number of studies necessarily precludes definitive and strongly

worded conclusions about the statement and suggests that read-

ers of this literature must be cautious as they explore this area.

Additionally, the small number of analyses automatically must

make one skeptical as to the generalizability of the observations

described in reports of these studies.



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Evidence

Epidemiology of health care–associated candidemia. Two re-

ports either directly or indirectly explored this question [160,

161]. In general, these studies suggest that health care–asso-

ciated candidemia exists as a distinct entity. In a large surveil-

lance project focused on patients with candidemia presenting

to the emergency department, Sofair et al. [161] prospectively

evaluated all cases of candidal BSI in several hospitals in various

regions of the United States. This project was sponsored by the

CDC and represented a specific effort to grapple with the notion

of community-onset candidemia. These investigators had clear

criteria for defining a BSI caused by Candida as community

onset in origin. Of 1143 cases of candidemia evaluated, the

authors determined that 356 (31%) were community-onset in-

fections [161].

More importantly, these investigators determined the prev-

alence of select risk factors for candidemia in persons with

community-onset disease. A review of the distribution of these

risk factors reveals that the vast majority of these community-

onset cases of candidemia did, in fact, represent HAIs. For

example, 1 in 5 subjects had underlying malignancy, and more

than a quarter of the 365 persons were receiving immunosup-

pressive therapy [161]. More strikingly, approximately half of

patients with community-onset infection had central venous

catheters in place. With respect to the distribution of specific

species causing candidemia, patients with community-onset in-

fection were less likely than were persons with traditional nos-

ocomial infection to have Candida albicans implicated. Addi-

tionally, 25% of community-onset infections were due to

Candida glabrata—a rate no different from the one seen in the

traditional nosocomial candidemia cases.

Exploring the question of health care–associated candidemia

from a different perspective, Shorr et al. [160] reviewed a large

administrative database to determine the general prevalence of

health care–associated BSIs. They defined health care–associ-

ated BSI as a BSI case diagnosed within 2 days after infection

that had any of the following conditions: the patient was ad-

mitted from a nursing home, had been hospitalized in the past

30 days, was being given treatment with immunosuppressive

therapy, had active malignancy, or was receiving chronic he-

modialysis. Among nearly 7000 blood-culture–confirmed cases

of BSI, health care–associated processes accounted for nearly

55% [160]. Nearly 2% of health care–associated BSIs were due

to yeast [160]. This rate of fungal BSI was lower than the rate

of fungemia noted in nosocomial BSI. However, since the rate

was not zero, it indicated that the proposed definition for health

care–associated fungemia does capture a unique population of

patients. Conversely, these data underscore the relative infre-

quency of this condition, given the huge number of BSI cases

seen annually in emergency departments in the United States.

Implications of failure to treat candidemia. Over the past

5 years, multiple analyses have documented that failure to

promptly treat serious infections increases a patient’s proba-

bility of death [70, 79, 82, 162]. This finding has been confirmed

for multiple disease states, from VAP to severe sepsis and septic

shock [70, 79, 82, 162]. The relationship between mortality and

either a delay in initial antibiotic therapy or the administration

of inadequate therapy also applies if one focuses on specific

pathogens (e.g., MRSA), rather than on clinical syndromes [5].

The definitions used for inadequate therapy generally categorize

this as the administration of an anti-infective agent to which

the culprit pathogen is resistant in vitro.

For candidemia, only 2 reports attempted to address the

relationship between inadequate or delayed antifungal therapy

and survival [91, 92]. A potential explanation for the existence

of so few reports dealing with this topic is the fact that in vitro

susceptibilities for antifungal agents are not well described and

that controversy exists regarding what represents in vitro

“resistance.”

In a retrospective analysis, Morrell et al. [92] reviewed 157

cases of candidemia. Their aims were to determine predictors

of outcome in this disease and to describe the relationship

between survival and both delays in antifungal therapy and

inadequate antifungal treatment. Two analyses were conducted;

the primary analysis included all antifungals, and a secondary

analysis evaluated patients infected with C. albicans, Candida

parapsilosis, or Candida tropicalis generally susceptible to flu-

conazole. The results were not stratified by organism type. Ap-

proximately half of the patients were infected with a non–C.

albicans species, and nearly 1 in 5 cases was attributed to either

Candida krusei or C. glabrata [92]. They defined delayed ther-

apy as administration of an antifungal agent 112 h after the

patient’s initial blood culture specimen was drawn. Inadequate

therapy represented use of fluconazole for infections due to C.

krusei. Specific MIC90 breakpoints were not determined. Overall

mortality approached 30%, which is similar to the death rate

for candidemia described in other reports [92]. For example,

in the analysis by Sofair et al. [161] noted above, the death rate

for candidemia exceeded 25%.

Of the 157 patients, only 5 received timely and adequate

antifungal therapy. Strikingly, the death rate among patients

given adequate treatment within 12 h after the blood culture

specimens were drawn was only 10% [92]. Among persons

given antifungal therapy beyond this 12-h window, the mor-

tality rate increased to 33% ( ) [92]. More importantly,P p .169

when stratifying the time to therapy into the periods of 12–24

h, 24–48 h, and 148 h after blood culture specimens were

drawn, these authors saw no difference in mortality. In mul-

tivariate analysis, a delay in antifungal treatment independently

doubled a patient’s risk of death.

Confirming these observations, Garey et al. [91] reviewed

230 cases of candidemia at 4 different centers. The crude mor-



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tality rate in this cohort was 30%. Of note, all subjects were

given treatment with fluconazole. These authors determined

that persons given fluconazole on the day the culture specimen

was obtained faced a mortality risk of 15%. They also observed

a stepwise increase in probability of death as time progressed

( ). Specifically, persons given treatment on the dayP p .0009

after the culture specimen was drawn had a mortality rate of

25%, whereas those who were finally given fluconazole �3 days

after the culture specimen was drawn had a 40% unadjusted

chance for in-hospital death [91]. In their logistic regression,

delay in therapy heightened the potential for death by 50%

(AOR, 1.50; 95% CI, 1.09–2.09) [91]. This relationship per-

sisted even after exclusion of persons for whom fluconazole

may have been inadequate on the basis of a definition similar

to the one employed by Morrell et al. [92].

Is risk stratification possible? Numerous reports detail po-

tential risk factors for fungemia [158, 159]. These range from

patient variables, such as a history of recent abdominal surgery

and underlying malignancy, to process of care issues, including

presence of a central venous catheter or receipt of parenteral

nutrition [158, 159]. Unfortunately, efforts to develop a specific

risk score that identifies persons with fungemia as the likely

cause of their syndrome have been fraught with limitations.

Often 2 approaches are employed—one relying on the presence

of certain risk factors, and the other using surveillance for

Candida colonization. Use of risk scores tends to compromise

specificity for the sake of sensitivity. In other words, although

a proposed score may identify a cohort of persons more likely

to have candidemia, the rate of candidemia remains sufficiently

low, and it can be presumed that clinicians would need to give

treatment to many patients without candidal infection to ensure

that they were capturing cases of candidemia. Alternatively,

surveillance-based strategies are necessarily cumbersome and

are unlikely to be of value for treatment of health care–asso-

ciated candidemia, because the patient is, by definition, pre-

senting to the emergency department and has not been in the

hospital long enough to have had surveillance cultures

performed.

A report by Leon et al. [163] represents a recent attempt to

refine the risk-score paradigm. In a multicenter trial in Spain,

these investigators studied 1669 persons who stayed in the ICU

for at least 7 days. The overall rate of candidemia was 6%

[163]. Specific variables associated with subsequent ICU-onset

candidemia included recent surgery, underlying severe sepsis,

use of parenteral nutrition, and known Candida colonization

[163]. Researchers developed a complex point-scoring tool

based on logistic regression, which employed good screening

characteristics for candidemia. Based on the plot of the receiver

operating curve, their score had an area under the curve of

0.85 [163]. However, this score has not been independently

validated in other settings or in other studies. Furthermore, for

the purposes of determining who might be at greater risk for

health care–associated fungemia, their score may not be ap-

plicable, because it incorporates the findings from surveillance

cultures.

Addressing colonization in particular, Pairroux et al. [164]

explored a role for the colonization index in determining the

potential for candidemia. Again, admittedly, this strategy will

not be helpful in the emergency department. However, for

completeness, readers should familiarize themselves with this

paradigm. These researchers completed a before-after study re-

lying on the colonization index. They computed the coloni-

zation index as the number of sites on a patient that tested

positive for Candida divided by the total number of sites

swabbed. Swabbing was done biweekly. If the colonization in-

dex was 10.4, these patients were given preemptive therapy

with fluconazole. With this technique and strategy, they were

able to significantly reduce rates of proven ICU-acquired can-

didemia (from 2.2% to 0%; ) [164].P ! .001

There were no specific reports investigating risk stratification

in health care–associated or community-onset fungemia. This

is perhaps not surprising, given the overall limited literature

on this topic.

Grading of Evidence


members agreed that the nature of the evidence available to

support this statement was category II (table 3).

Level of Support




voted to accept the statement with major reservations, and 9%

voted to reject the statement with reservations. None rejected

the statement completely. In comparison, of the 744 IDSA






pletely (figure 10).

Discussion

This statement should be viewed as complementary to the oth-

ers in this supplement, addressing both particular pathogens

and specific HAI syndromes. For the concept of HAI to prove

meaningful, it must be internally consistent. Thus, if one lim-

ited the health care–associated stratification to bacterial path-

ogens only, the entire notion might prove both difficult to apply

and unhelpful. Therefore, recognition that, even for fungal BSI,

the health care–associated concept is unique reinforces the sup-



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Figure 10. Voting comparison for statement 8 (“Patients with seriousHAIs who have risk factors for fungal infections require early empiricantifungal therapy to reduce mortality”). “IDSA” refers to the membersof the Infectious Diseases Society of America who responded to a Web-based survey; “Summit” refers to the Health Care–Associated Infection(HAI) Summit panel.

port for the need to adopt HAIs as distinct syndromes. Al-

though there is certainly overlap between community-acquired,

health care–associated, and nosocomial processes, the evidence

consistently underscores the need to break our traditional di-

chotomous classification scheme into 3 distinct components.

Unfortunately, there are only 2 analyses that specifically ad-

dress the epidemiology of health care–associated candidal BSIs

[160, 161]. These studies, however, were internally valid and

well conducted. Thus, clinicians should at least recognize the

potential for candidemia to be a cause of BSI in patients pre-

senting to the emergency department. This statement is not

meant to imply that physicians should prescribe antifungal

treatment either routinely or reflexively. Instead, local epide-

miologic information must be gathered to facilitate the devel-

opment of local protocols to determine whether Candida spe-

cies are an issue of concern. Readers should also note that there

are no data suggesting that health care–associated candidemia

does not exist. In other words, there are no studies that spe-

cifically disprove this assertion.

For risk stratification, one must rely on clinical judgment.

No reliable tool exists to help determine which patients face

an elevated potential for candidemia. Given the pathophysi-

ology of the process, it appears that immunosuppression or

presence of a central venous catheter is necessary, but neither

is a sufficient condition for this disease. Perhaps, therefore, in

giving treatment to persons presenting with a syndrome con-

sistent with severe sepsis but not showing evidence of pul-

monary infection (or other evident infection), clinicians should

consider more formally candidal BSI in the differential diag-

nosis, particularly if multiple risk factors, including those noted

above, are present. However, this recommendation represents

opinion more than fact but does acknowledge that failure to

promptly and adequately treat fungal BSI leads to substantial

excess mortality. Conversely, one cannot hope to begin anti-

fungal therapy promptly if one presupposes that yeast can never

be a cause of health care–associated BSI. Given that it seems

that the vast majority of patients are not given prompt treat-

ment, it appears there is ample room for improvement.

Future Directions

Certainly, more broadly designed prospective epidemiologic re-

search is required. Such projects must include a range of in-

stitutions, rather than a focus exclusively on academic centers.

With such information, geographic variations may become ap-

parent. More importantly, these surveillance studies can si-

multaneously collect information that allows for the develop-

ment and validation of risk-stratification tools. Finally, other

diagnostic measures are needed. Since cultures for Candida may

take several days to grow, clinicians require more-rapid diag-

nostic interventions to determine whether to continue or stop

presumptive antifungal treatment.

STATEMENT 9: ALL INFECTIONS INIMMUNOCOMPROMISED PATIENTS SHOULDBE CONSIDERED HAIs UNTIL PROVENOTHERWISE


Infection due to a diverse spectrum of pathogens is the most

common and well-recognized complication in patients with

compromised immunologic host defenses as well as a native

disease and/or iatrogenic interventions. The microbial etiology

for such infections may vary across different specific immune

defects, severity and duration, and other modifiers, including

the patient’s prior and present geographic location, prior ex-

posure to anti-infectives for prophylaxis or treatment, and ex-

ogenous exposures (e.g., transfused blood products or donor

organs). The orthodox view pertaining to the origin of infec-

tions in immunocompromised hosts recognizes that the incit-

ing organism(s) may originate from (1) the patient’s native

endogenous flora or dormant organisms, which become re-

activated with failed immune defenses; (2) endogenous flora,

which has been modified principally by exposure to anti-in-

fective agents or the animate and inanimate nosocomial en-

vironment; (3) exogenous reservoirs; and (4) as-yet-unknown

sources. Among organ transplant recipients, the donor organ

represents another reservoir for pathogen transmission. Al-

though much of the important clinical management of im-

munocompromised patients occurs within the hospital unit or

the critical care setting, some of the management has shifted

to the parahospital or outpatient health care facilities. Promi-

nent examples include outpatient chemotherapy for oncologic

disease, management of HIV-associated illness, and long-term–

acute care facilities that receive organ transplant recipients for

ventilator dependence or rehabilitation. HAIs within this ex-

panded sphere might have a greater impact on the immuno-

compromised host than on immunocompetent patients and

also may be caused by a different spectrum of pathogens. With



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respect to MDR bacteria, the duration of antecedent coloni-

zation and the incidence of progression to infection are 2 pa-

rameters that may have a greater impact on immunocompro-

mised patients. This section focuses on whether there is

evidence in the literature confirming that the health care en-

vironment is the exclusive source of all infections in the im-

munocompromised host.

Methods

A literature search of the PubMed database was performed on

15 September 2007, and results were narrowed to the English

language and human subjects. The purpose of the search was

to identify published articles on the epidemiology of infection

among immunocompromised hosts and, specifically, to deter-

mine whether the inciting pathogens were acquired in a com-

munity, health care, or hospital setting. The initial search terms

and combinations included “immunocompromise AND

healthcare-associated infection,” which yielded 656 articles;

“immunocompromise AND infection AND epidemiology,”

which yielded 1971 articles; and “immunocompromise AND

community-acquired infection,” which yielded 127 articles.

Only articles that included major immunocompromised host

categories (bone marrow or solid organ transplant recipients

and patients with cancer, neutropenia, granulocytopenia, or

AIDS) were selected for further review. After examinination of

all articles for these criteria, a total of 12 articles were deemed

relevant to the statement.

A second PubMed search for specific MDR pathogens of

interest (S. aureus, Enterococcus, P. aeruginosa, Candida, and

Aspergillus) was combined with “immunocompromised” and

was limited to the English language only. The search terms

“immunocompromise AND antimicrobial resistance” yielded

225 articles, “methicillin-resistant Staphylococcus aureus”

yielded 110 articles, “immunocompromise AND Enterococcus”

yielded 84 articles, “immunocompromise AND Candida”

yielded 970 articles, and “immunocompromise AND Aspergil-

lus” yielded 904 articles. Since prolonged colonization with such

organisms may represent a more sensitive end point when the

presence of health care acquisition is discerned, all the organ-

ism-specific searches were also combined with the term

“colonization.”

Evidence

Is the health care environment the exclusive source for all

infections in immunocompromised patients? Not all infec-

tions in immunocompromised patients are the result of health

care exposures; some patients become colonized and infected

with pathogenic organisms as a result of their weakened im-

mune status. Kotton et al. [165] mentioned numerous reports

of transmission of zoonosis to humans during and after solid-

organ and hematopoietic stem cell transplantation. The ma-

jority of zoonoses cases are acquired after transplantation. Cer-

tain occupations (e.g., veterinarian, farmer, and forestry

worker), pet ownership, hobbies (e.g., hunting), and travel also

increase the risk of acquisition [166]. Lamaris et al. [167] also

reported the incidence of Scedosoprium infections among 21

patients with cancer in 1989–2006. The authors concluded that

these infections were associated with typical immunologic de-

fects, such as hematologic cancer, neutropenia, lymphopenia,

and systemic steroid use. Although an increase in the incidence

was seen in the last 5 years of the study, there was no evidence

of nosocomial transmission.

Does immunocompromise contribute independently to the

alteration of the epidemiology of HAI? Several articles in-

vestigated whether there are significant differences in the eti-

ology of infection between immunocompromised and non-

immunocompromised hosts. A study by Shorr et al. [160] of

a 2-year database of BSIs, which were subsequently classified

as community-acquired, health care–acquired, or hospital-ac-

quired infection, demonstrated only minimal differences in the

etiology between immunocompromised patients ( )n p 2140

and immunocompetent patients ( ). When all acqui-n p 4557

sition categories were analyzed, no significant differences in the

incidence of any gram-positive pathogen were observed.

Among gram-negative organisms, the incidences of Pseudo-

monas species (4.0% vs. 2.3%; ) and Klebsiella speciesP p .001

(8.2% vs. 5.1%; ) were significantly higher among im-P ! .001

munocompromised patients than among nonimmunocom-

promised patients [160].

A study by Dimiopoulos et al. [168] compared the charac-

teristics of candidemia between immunocompromised (n p

) and immunocompetent ( ) patients. The mean time9 n p 15

from hospitalization to diagnosis of candidemia was 9 days

(range, 5–11 days). With respect to risk factors, no important

differences were observed between the 2 cohorts [168].

Immunosuppression was not found to be a significant risk

factor for all MDR bacterial infections in the ICU in a retro-

spective, matched, case-control study of 256 medical/surgical

ICU patients [169]. With the notable exception of MRSA, which

was significantly more frequent in the immunosuppressed co-

hort (25 of 44 vs. 10 of 26; ), there was no independentP p .01

association between immunosuppression and ICU-acquired

MDR organisms.

Does immunocompromise contribute to a higher incidence

of MDR colonization and thus act as a precursor to HAI?

Several studies have examined the incidence of MDR coloni-

zation among immunocompromised patients. In a prospective

observational study of 2347 admissions in 14 French ICUs,

nasal and cutaneous swab screening was performed to deter-

mine the variables associated with MRSA carriage at the time

of ICU admission [170]. Immunosuppression was not associ-

ated with an increased risk of MRSA carriage. Furuno et al.



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[171] confirmed that risk factors other than immunosuppres-

sion identified patients colonized with antibiotic-resistant bac-

teria. They found that previous hospital admission occurring

within 1 year before the time of current hospitalization was

independently associated with a high risk of carriage of anti-

biotic-resistant bacteria. Nseir et al. [169] conducted a retro-

spective case-control study to determine the relationship be-

tween immunosuppression and ICU-acquired MDR bacteria

(MRSA, ESBL-producing organisms, and MDR P. aeruginosa,

Acinetobacter baumannii, and Stenotrophonmonas maltophilia).

In univariate analysis, immunosuppressed patients had a higher

incidence of colonization with these organisms than did im-

munocompetent patients (22 per 1000 patient-days vs. 12 per

1000 patient-days; ); however, in multivariate analysis,P p .004

antibiotic treatment administered before or during the ICU stay

remained a significant factor. A 6-year study by Reddy et al.

[172] examined the results of rectal swab screening for ESBL-

producing gram-negative bacilli in 17,872 patients hospitalized

in high-risk units. Notably, the medical ICU service had the

highest incidence of colonization with ESBL-producing organ-

isms during the study period, whereas the hematology/oncology

and solid-organ transplant units experienced significantly lower

incidences.

Does immunocompromise contribute to a prolongation of

MDR colonization and thus act as a precursor to HAI?

There is limited evidence examining the duration of MDR col-

onization in immunocompromised patients. Most of the avail-

able evidence focuses on duration of colonization with van-

comycin-resistant enterococci (VRE). The reports that have

demonstrated a prolonged duration of VRE gastrointestinal col-

onization have studied immunocompromised patients, such as

abdominal solid-organ recipients and oncologic patients with

or without neutropenia [173–175]. One study by Montecalvo

et al. [173] determined that 86 oncologic patients with VRE

colonization were identified. Colonization was persistent for 17

weeks in the majority of patients. Of 34 colonized patients

discharged from and then readmitted to the hospital after a

mean of 2.5 weeks, 22 (61%) were still colonized with VRE.

PFGE further demonstrated that VRE colonization with the

same strain could persist for at least 1 year. In a similar patient

population, Roghmann et al. [175] found a 44% rate of per-

sistent VRE colonization. Patel et al. [174] reported the results

of serial rectal surveillance cultures from 52 liver and kidney

transplant recipients during both inpatient and outpatient pe-

riods and followed up for a median of 306 days. Persistent VRE

colonization was present in 150% of the initial cohort.

Are there infections in immunocompromised hosts that arise

from distinct community reservoirs or from shared reservoirs

between the community and the health care setting? There

is ample evidence that the same pathogen can originate from

both community and health care settings. Representative ex-

amples found in the search included Legionella species, My-

cobacterium tuberculosis, Aspergillus species and other mycelial

organisms, influenzae viruses, varicella-zoster virus, and respi-

ratory syncytial virus [167, 176–178]. Pneumocystis, on oc-

casion, can be acquired as a nosocomial pathogen. Organisms

that appear to be acquired exclusively in the community setting

include Listeria monocytogenes, Nocardia species, Cryptococcus

neoformans, endemic mycoses, Pneumocystis jiroveci, Toxo-

plasma gondii, Strongyloides stercoralis, and other parasites, as

well as pathogens causing zoonotic infections [165].

Grading of Evidence


workshop members voted that the evidence to support the

statement was category II, 20% voted category III, and 60%

voted category V (table 3).

Level of Support

Overall, 0% of the summit participants voted to accept the state-

ment completely, 0% voted to accept the statement with some

reservations, 27% voted to accept the statement with major res-


and 27% voted to reject the statement completely. In comparison,

of the 744 IDSA members who participated in the online survey,

11% voted to accept the statement completely, 28% voted to

accept the statement with some reservations, 15% voted to accept

the statement with major reservations, 27% voted to reject the

statement with reservations, and 19% voted to reject the state-

ment completely (figure 11).

Discussion

Although the epidemiology of infection among immunocom-

promised patients has been studied intensively and reported

for decades, there are few, if any, studies that pinpoint the

precise time and location when the pathogen is acquired (other

than rare and well-documented epidemic outbreaks). Thus,

many of the diverse organisms that can cause infection in the

immunocompromised host are presumptively classified as com-

munity associated, hospital associated, or health care associated,

on the basis of the known ecology (i.e., natural reservoirs and

vectors), biology (i.e., incubation period and latency), and ep-

idemiology (i.e., presence of geographic or temporal clusters

supported by molecular typing methods that match the or-

ganism patient-to-patient or between a patient and an envi-

ronmental source) of the pathogen in question.

The paucity of precise investigations in this area necessitated

a somewhat oblique approach to the literature search. Not sur-

prisingly, the search effort produced a very low level of evidence

in support of the statement that all infections should be con-

sidered health care–associated among immunocompromised

patients. It is reasonable to assume that (1) immunocompro-



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Figure 11. Voting comparison for statement 9 (“All infections in immunocompromised patients should be considered HAIs until proven otherwise”).“IDSA” refers to the members of the Infectious Diseases Society of America who responded to a Web-based survey; “Summit” refers to the HealthCare–Associated Infection (HAI) Summit panel.

mised patients are exposed more intensively to the health care

setting after or between hospitalizations than are immunocom-

petent patients and (2) residual effects of health care exposure

could lead to health care acquisition of a finite number of

pathogens and infections attributable to those pathogens. How-

ever, with regard to MDR bacteria, the available literature fails

to show an independent association of immunocompromised

states with either colonization or infection with such pathogens.

Instead, such observations were mediated by more-dominant

mechanisms, such as antimicrobial exposure, intensity, and du-

ration of health care exposures, in which “immunocompro-

mise” was a surrogate marker. Although colonization-to-infec-

tion ratios may be quite high (particularly for low-virulence

pathogens, such as VRE), it was important to direct part of

the search effort to a “colonization” end point because mod-

ification of the patient’s endogenous microbial reservoirs is a

well-recognized antecedent condition to an overt infection

[179].

Future Directions

The idealized study prototype, which would allow a clear and

scientific conclusion as to whether a pathogen was health care

associated or non–health care associated among immunocom-

promised patients, requires sequential testing with a highly sen-

sitive and specific assay for the presence of the pathogen of

interest performed throughout periods of health care exposure

and non–health care exposure. The rapid development and

deployment of gene-based and other molecular diagnostic

methods as investigative tools to detect the presence of resis-

tance could be valuable in answering this intriguing question.

STATEMENT 10: ADJUNCTIVE THERAPYSHOULD BE UTILIZED TO PREVENT ANDTREAT SERIOUS HAIs


Serious infections are a leading cause of death in hospitalized

patients, with a mortality rate of up to 60% among patients

manifesting septic shock [180]. Adjunctive therapies targeted

to control the immunologic, inflammatory, and procoagulant

response elicited by infection have been researched and pre-

scribed for decades. In this section, we specifically review the

level of evidence supporting tight glycemic control, avoidance

of RBC transfusion, IVIG, and drotrecogin alfa (activated) as

adjunctive therapies for the treatment of HAIs, with emphasis

on the critically ill population.

Methods

A PubMed database search was conducted to identify relevant

reports involving each adjunctive therapy. The search strategy

was limited to humans, the English language, clinical trials,

randomized controlled trials, and meta-analyses. Text terms for

each adjunctive therapy—that is, “IVIG,” “IGIV,” “intravenous

immune globulin,” and “intravenous immunoglobulin”—were

combined using the “OR” function and then were combined

using the “AND” function with search terms describing HAI,

including “bacteremia,” “bloodstream infection,” “pneumo-

nia,” “nosocomial infection,” and “infection.” The search

yielded 88 articles for “tight glycemic control,” 29 articles for

“red blood cell transfusion avoidance,” 87 articles for “IVIG,”

and 88 articles for “drotrecogin alfa (activated).” Bibliographies

of selected articles were also reviewed to identify relevant

reports.

Evidence

Tight glycemic control. Hyperglycemia is a common occur-

rence in patients in the critical care setting, regardless of history

of diabetes mellitus. The etiology of hyperglycemia is multi-

factorial and may adversely affect immune function, such that

an inflammatory state is promoted and granulocyte adherence,

chemotaxis, phagocytosis, and intracellular killing are nega-

tively altered [181]. Control of hyperglycemia in the acute care

setting has been associated with prevention of sternal wound

infection and survival in patients undergoing cardiac surgery

procedures [182, 183].



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Limited data are available on controlling glucose levels and

outcomes in critically ill patients with HAI. Compelling data

on critically ill patients with or without infection were reported

in a prospective, randomized, controlled trial that considered

whether intensive insulin therapy (defined by targeted blood

glucose levels of 80–110 mg/dL) reduced ICU mortality among

1548 surgical ICU patients [184]. Compared with patients who

received conventional treatment (targeted blood glucose levels,

180–200 mg/dL), patients randomized to receive intensive in-

sulin therapy had significantly decreased rates of ICU mortality

(8.0% vs. 4.6%; ) and in-hospital mortality (10.9% vs.P ! .04

7.2%; ). The greatest reduction in mortality appearedP p .01

to be limited to patients who required �5 days of ICU care

and may have been linked to infection prevention, as indicated

by a marked reduction in deaths due to multiple organ failure

secondary to sepsis and in rates of septicemia. Not surprisingly,

hypoglycemia occurred in 39 patients in the intensive-treatment

group and in 6 patients in the conventional-treatment group.

A follow-up trial involving 1200 adult medical ICU patients

conducted by the same group of investigators using identical

methodology revealed similar findings [184, 185]. Although the

intention-to-treat in-hospital mortality was not statistically dif-

ferent between groups, the subgroup of patients requiring �3

days of ICU care and randomized to receive intensive insulin

therapy had significantly increased hospital survival, compared

with patients in the conventional arm (57% vs. 47%; P p

). The occurrence of hypoglycemia, defined as a blood.009

glucose level !40 mg/dL, was alarmingly high in the group

receiving intensive insulin therapy (25.1% vs. 3.9%; ).P ! .001

A retrospective evaluation of the effects of tight glycemic con-

trol on critically ill patients with sepsis at the time of admission

found no difference in the in-hospital or ICU mortality among

all patients; however, a survival advantage was observed among

patients requiring �3 days of ICU care plus intensive insulin

therapy (OR, 2.9; 95% CI, 1.8–4.6; ) [186]. FurtherP ! .001

evaluation of the impact of hypoglycemia in the subgroup of

patients with sepsis at ICU admission found it to be indepen-

dently associated with in-hospital mortality (AOR, 2.8; 95%

CI, 1.8–4.2; ). This finding has been confirmed in aP ! .001

separate evaluation [187].

Avoidance of RBC transfusions. Transfusion of packed

RBCs (PRBCs) is a common intervention for critically ill pa-

tients. For patients with severe sepsis, PRBC transfusion has

become part of a widely adopted resuscitation algorithm used

in many hospitals and endorsed by the Surviving Sepsis Cam-

paign guidelines [10, 188–191]. The basis of this recommen-

dation and its subsequent implementation at the local level

stems from significantly improved survival in the landmark trial

of early goal-directed therapy [192]. However, whether trans-

fusion therapy is a key ingredient of improved outcomes for

patients with severe sepsis remains uncertain, and, when closely

scrutinized in all critically ill patients, this form of therapy may

be correlated with major nosocomial complications, most no-

tably infection.

The strongest evidence linking PRBC transfusion and nos-

ocomial infection comes from large observational trials and,

therefore, should not be interpreted as absolute proof of hy-

pothesis. Nonetheless, the accumulated data consistently point

to a direct relationship between transfusion and infectious com-

plications. The CRIT trial—a prospective, observational study

of transfusion practices in the United States conducted over a

10-month period in 2000 and 2001—evaluated 4892 patients

in 284 distinct ICUs [193]. Within this population, 3502 pa-

tients were free of BSI at baseline, as well as 48 h after en-

rollment, and were secondarily evaluated for the development

of BSI [194]. Of the patients, 49% received transfusion and

3.3% developed a BSI during the 30-day evaluation. Patients

who were found to develop BSI were significantly more likely

to receive PRBC transfusion (76.1% vs. 48.7%; ) andP ! .001

to have a greater number of units transfused (4.0 � 4.6 U vs.

2.3 � 4.3 U; ), compared with patients without thisP ! .001

infectious complication. In multivariable analysis, transfusion

was found to significantly increase the likelihood of BSI (AOR,

2.23; 95% CI, 1.43–3.52; ), and the probability increasedP ! .001

as the number of PRBC units transfused increased. Using the

same CRIT study population, a subgroup of 1518 patients who

required mechanical ventilation for at least 48 h were evaluated

for the development of VAP [195]. Overall, 52.7% of patients

receiving mechanical ventilation received transfusion, and

22.6% received a diagnosis of VAP. Similar to findings of the

aforementioned BSI analysis, patients with VAP were signifi-

cantly more likely to receive transfusion (58.2% vs. 51.4%;

), and transfusion was an independent predictor of VAPP p .03

development in the multivariable analysis (AOR, 1.89; 95% CI,

1.33–2.68; ). A single-center, prospective, observa-P p .0004

tional cohort of 2085 mixed medical/surgical ICU patients

found that patients who received transfusion ( ) had an p 428

significantly higher incidence of nosocomial infection (14.3%

vs. 5.8%; ), longer length of ICU stay (8.2 � 11.7 daysP ! .001

vs. 3.3 � 5.1 days; ), longer length of hospital stayP ! .001

(18.3 � 18.7 days vs. 9.9 � 9.5 days; ), and higher in-P ! .001

hospital mortality rate (10.2% vs. 21.8%; ), comparedP ! .001

with patients who did not receive transfusion [196].

Drotrecogin alfa (activated). The use of drotrecogin alfa

(activated), the recombinant form of human activated protein

C, as an adjunctive therapy for infections manifesting as severe

sepsis and septic shock has been widely studied. The question

of which patient subgroup is most likely to benefit from the

therapy and, at the same time, be protected from drug toxicity,

most notably bleeding, remains largely unresolved. Collectively,

4 large industry-sponsored trials form the basis for bedside

decision-making regarding the use of drotrecogin alfa (acti-



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vated) for adults [114, 197–199]. In each trial, ∼75% of patients

presented from the community, and among 50% of these pa-

tients, the lung was the site of infection. The FDA-approved

labeling for drotrecogin alfa (activated) is derived from the

initial landmark trial, PROWESS [114]. In this trial of 1690

patients with severe sepsis or septic shock, a 6.1% absolute risk

reduction in mortality was observed that favored drotrecogin

alfa (activated) over placebo; however, the benefit appeared to

be limited to the patient subgroup that had a higher severity

of illness, as indicated by an APACHE II score of �25 [200,

201]. Additional subgroup analysis of this trial revealed that

patients with severe CAP given treatment with drotrecogin alfa

(activated) were also statistically more likely to survive [202].

The lack of efficacy for patients with a low severity of illness,

as indicated by an APACHE II score of !25 or by single-organ

dysfunction, was confirmed in a follow-up trial that was halted

because of therapeutic futility found by an interim analysis

[197].

Two initial, randomized, placebo-controlled trials demon-

strated consistent bleeding rates. In contrast, an open-label trial

of 2375 patients who received drotrecogin alfa (activated) re-

vealed higher rates of serious bleeding during the 96-h infusion

period and the 28 days after drug initiation in a noncontrolled

setting [199]. These results, coupled with a higher number of

CNS bleeding events observed with administration of drotre-

cogin alfa (activated), compared with placebo, during the in-

fusion (27 events vs. 3 events) and after 28 days (60 events vs.

6 events) in the accumulation of the 4 largest trials to date,

indicate that the serious bleeding risk posed by drotrecogin alfa

(activated) requires careful consideration before prescribing,

particularly for patients with severe thrombocytopenia or men-

ingitis [203].

IVIG. IVIG in polyclonal form has been extensively studied

as an adjuvant therapy for severe infections. The complete

mechanism of action is unknown, but the fundamental phar-

macology of IVIG is activity against bacterial products, includ-

ing endotoxin, other superantigens, and host cytokines. Re-

cently, 3 meta-analyses have been published on the use of

polyclonal IVIG for critically ill adult patients with sepsis, severe

sepsis, or septic shock [204–206]. Despite the heterogeneous

patient populations, as well as variable dosing, duration, and

product composition, each evaluation found IVIG to be as-

sociated with a significant survival benefit. However, when only

high-quality trials (randomized, double-blind, placebo-con-

trolled trials) are considered in the meta-analysis, the associ-

ation with improved survival does not exist [205, 206]. This

finding is consistent with recently published high-quality trials.

The Score-Based Immunoglobulin Therapy of Sepsis study

found no difference in 28-day mortality between patients given

a 2-day course of intravenous IgG and patients given placebo

(39.3% vs. 37.3%; ) [207]. Likewise, a trial of IgMA-P p .67

enriched immunoglobulin compared with placebo for neutro-

penic patients with sepsis caused by gram-negative organisms

( ) found no difference in mortality at 28 days (26.2%n p 211

vs. 28.2%; ) [208]. Additionally, it appears that poly-P p .93

clonal IVIG is of limited benefit relative to placebo in targeting

specific populations, including patients with streptococcal toxic

shock syndrome and intra-abdominal sepsis [113, 209].

Grading of Evidence

On the basis of a review of the literature cited above, workshop

members voted that the nature of evidence for the statement

ranged from category I to category IV (table 3).

Level of Support

Overall, 9% of the summit participants voted to accept the state-

ment with some reservations, 73% voted to accept the statement

with major reservations, and 18% voted to reject the statement

with reservations. In comparison, of IDSA members who com-

pleted the online survey, 18% voted to accept the statement

completely, 40% voted to accept the statement with some res-

ervations, 23% voted to accept the statement with major res-


and 0% voted to reject the statement completely (figure 12).

Discussion and Future Directions

This role of adjunctive therapies for the treatment of HAI re-

mains unclear, as demonstrated by the summit participants and

IDSA membership. Summit participants did concede that there

is evidence that tight glycemic control reduces ICU mortality

and that the incidence of bacteremia, VAP, and mortality is

related to RBC transfusions. However, there is inadequate evi-

dence for and controversy regarding the use of activated protein

C and IVIG as adjunctive therapies for the treatment of HAI.

The lack of consensus can be traced to the heterogeneous nature

of infections and patient populations. Therefore, translation of

the results of the cumulative literature for bedside care remains

a patient-by-patient decision. The practice of tight glycemic

control, avoidance of PRBC transfusion, and use of drotrecogin

alfa (activated) or IVIG for patients with HAI will become more

universal only with more succinctly defined clinical targets,

standardized preparations, and, perhaps, disease-state bio-

markers identifying patients who would most likely benefit

from adjunctive therapies.

CONCLUSIONS

HAIs should be viewed as distinct infections that identify in-

dividuals with an increased risk of infection with MDR path-

ogens. The current level of evidence is such that this idea ap-

pears to be best supported for HCAP and health care–associated

BSIs. Other infections, including intra-abdominal, skin, uri-

nary-tract, CNS, and pediatric infections, have not been as well



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Figure 12. Voting comparison for statement 10 (“Adjunctive therapy should be utilized to prevent and treat serious HAIs”). “IDSA” refers to themembers of the Infectious Diseases Society of America who responded to a Web-based survey; “Summit” refers to the Health Care–AssociatedInfection (HAI) Summit panel.

studied, and definitive statements regarding HAI for these cat-

egories await the findings of future studies. However, it appears

prudent to identify patients at risk for infection with MDR

pathogens or any other type of infection, to increase the like-

lihood of administration of appropriate empirical antimicrobial

therapy.

Initial treatment with an appropriate antimicrobial regimen

is associated with reduced risk of death and more–cost-effective

medical care during hospitalization. To provide appropriate

empirical therapy, clinicians must actively identify risk factors

for colonization or infection with MDR pathogens in the pa-

tients for whom they provide treatment. Classification of the

patient as at risk for HAI is a surrogate marker for increased

risk of colonization and infection with MDR bacteria. At the

same time, clinicians must develop and implement strategies

in their hospitals to ensure that unnecessary antimicrobial usage

is avoided, to minimize the emergence of antibiotic resistance.

The de-escalation strategy is one that attempts to accomplish

this dual goal by providing for the administration of broad-

spectrum empirical antimicrobial therapy to patients at risk for

MDR infection while modifying the empirical antimicrobial

regimens on the basis of microbiological, antimicrobial-sus-

ceptibility, and clinical-response data. De-escalation also im-

plies that the shortest antimicrobial regimen deemed appro-

priate for a patient’s infection and clinical response should be

employed. This strategy is intended to improve short-term out-

comes for individual patients and long-term outcomes for the

general population.

The goal of the HAI Summit was to critically appraise ex-

isting literature, to assess the relative strengths and limitations

of our current knowledge in this area. A recurring theme, re-

gardless of which statement was being discussed, was the pau-

city of specific data concerning HAIs and the frequent extrap-

olation of data from studies of nosocomial infections. The

“Treatment by Sites of Infection” workshop showed that only

HCAP and health care–associated BSI have been directly eval-

uated as separate distinct clinical entities. However, even for

these infections, it is apparent that additional studies are needed

to define the criteria for and definition of HAI. For other in-

fections, including skin and intra-abdominal infections, inves-

tigations evaluating patients at risk for HAI are needed. One

assumption made by the HAI Summit members is that the

criteria for HAI are similar for all the infections examined.

However, this may not be correct, and there is room for debate

regarding which patient subsets should be included. For ex-

ample, the presence of a device such as a joint prosthesis could

be an unexplored criterion for health care–associated BSI, but

this might not be the case for HCAP. Clearly, there is overlap

among all these infections in terms of distinguishing HAI from

community-acquired infection. Nevertheless, additional studies

are needed to validate these statements.

In the “Treatment by Organism” workshop, these complex

concerns translated into discrepant opinions regarding the op-

timal approach to the administration of empirical therapy to

patients at risk for HAI. Again, the theme of antimicrobial de-

escalation emerged as a unifying concept, regardless of infection.

However, the specific agents employed for initial antimicrobial

treatment of HAI could vary, depending on the site of infection.

Additionally, the need to provide specific coverage for distinct

pathogens (MRSA and Candida species) in patients at risk for

HAI also led to much discussion and debate. These discussions

focused on the need to balance empirically covered MDR path-

ogens through the use of broad-spectrum therapy while mini-

mizing the generation of more resistance through unnecessary

antibiotic use. An example is the need to provide double coverage

for suspected HAI caused by gram-negative bacteria. Adding an

aminoglycoside to a b-lactam or carbapenem is likely to increase

overall coverage, compared with the addition of a fluoroquin-

olone. However, unnecessary use of dual coverage could also

promote more antimicrobial resistance.

At the summit’s conclusion, participants identified several

areas of research that merit priority to refine our care of patients

with HCAP. Large-scale, multicenter, observational cohort

studies with rigorous microbiological data are needed to better



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define the precise subsets of patients at risk for infection with

MDR pathogens, as well as to better delineate risk factors for

specific pathogens. Similar studies are needed regarding the

implications of severity of illness for outcomes. In addition, a

clear need exists for specific studies on antibiotic therapy de-

escalation, specifically according to pathogen species, and the

optimal duration of therapy. Investigators should be actively

encouraged to pursue these lines of investigation in the future.

Acknowledgments

Supplement sponsorship. This article was published as part of a sup-plement entitled “Health Care–Associated Infection (HAI): A Critical Ap-praisal of the Emerging Threat—Proceedings of the HAI Summit,” sponsoredby Medical Education Resources and Consensus Medical Communicationsand supported by an unrestricted educational grant from Ortho-McNeil, Inc.,administered by Ortho-McNeil Janssen Scientific Affairs, LLC.

Potential conflicts of interest. M.H.K. has received grants/researchsupport from Pfizer, Merck, and Bard. V.G.F. has received grants/researchsupport from Cubist, Theravance, Merck, and Nubi Inhibitex; has been aconsultant for Astellas, Cubist, Biosynexur, Theravance, Merck, and John-son & Johnson; and has been a speakers’ bureau participant for Cubistand Pfizer. S.T.M. has received grants/research support from Pfizer,AstraZeneca, Astellas, and Ortho-McNeil. J.J.R. has been a consultant forWyeth and Ortho-McNeil and has been a speakers’ bureau participant forWyeth and Ortho-McNeil. A.F.S. has received grants/research support formAstellas, GlaxoSmithKline, Johnson & Johnson, Pfizer, and Sanofi; has beena consultant for Astellas, GlaxoSmithKline, Johnson & Johnson, Pfizer, andSanofi; and has been a speakers’ bureau participant for Astellas, Glaxo-SmithKline, Johnson & Johnson, Pfizer, Sanofi, and Merck. J.S.S. has re-ceived grants/research support from Pfizer and has been a consultant forJohnson & Johnson, Roche, Novartis, Schering-Plough, and Bayer. D.L.S.has received grants/research support from Pfizer, Arpida, Cubist, andRoche. All other authors: no conflicts.

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