Prompting Appropriate Empirical Antimicrobial Therapy for Patients with Community-acquired Infections

Shey-Ying Chen, MDDepartment of Emergency

MedicineNational Taiwan University

HospitalAugust 14, 2007

Leading Causes of Death

USA, 2001 Flu and pneumonia (7th: 2.57%) Sepsis (10th: 1.33%)

Taiwan, 2002 Pneumonia (7th: 20.17/100,000, 3.17%) Sepsis (13th: 4.28/100,000, 0.76%)

(3.9 %)

(3.93 %)

Epidemiology of Severe Sepsis

Acute hospitalized patients in 847 USA hospitals, 1995

Estimate case number and incidence 751,000 cases (1.5% increasing yearly) Incidence

3 cases/1,000 population 2.26 cases/100 hospital discharge

51.1% required ICU care Mortality ： 28.6%

Estimate nation-wide cases: 215,000 desths 9.3% of all mortality of the year ， equal to AMI deaths

Crit Care Med. 2001;29:1303-1310

Incidence/Mortality in Severe Sepsis– Age

Crit Care Med. 2001;29:1303-1310

10% (children) ~ 38.4% (> 85 yrs)

0.2/1000 pop (children) ~ 26.2/1000 pop (> 85 yrs)

Mortality in Severe Sepsis - Comorbidity

Crit Care Med. 2001;29:1303-1310

Effective Therapies for Mortality Reduction

Inappropriate Antibiotics Use in Severe Community-acquired Bacteremia

Independent predictor for ICU mortality (OR, 4.11)

Attributable mortality increases as disease severity 10.7%: APACHE II

score < 15 41.8%: APACHE II

score ≧ 25Chest. 2003;123:1615-1624

Critical Patients Receiving Inappropriate Antibiotics Studies in ICU setting Inappropriate empirical antibiotics:

8.5%~17% Significant impact on

Survival Length of hospital stay Total hospital cost

Chest. 2003;123:1615-1624

Crit Care Med. 2003;31:2742-2751

Chest. 1999;115:462-474

Empirical Antibiotics Selection

Infection site Potential pathogen Hemodynamic stability - EGDT Risk of short-term mortality Possible presence of antimicrobial

resistance

Antimicrobial Resistance

Resistance Due to Selection

Spontaneous mutation occurs in the absence of drug selection in a sensitive population

Drug treatment

J Infect Dis 1986;154:792-800

Mutant is selected for by drug treatment as sensitive strains die off

Resistance becomes clinically manifested during therapy

Resistant clone grows within what used to be a sensitive population

Evolution of Antimicrobial Resistance

S. aureus

Penicillin

[1943]

Penicillin-resistant

S. aureus, [1944]

Methicillin

[1959]

Methicillin-resistant S.

aureus (MRSA), [1960]

Vancomycin-resistant

enterococcus (VRE), [1989]

Vancomycin[1997]

Vancomycin intermediate

resistant S. aureus, [1997]Vancomycin-ResistantS. aureus

[ ? ]

Risk of Nosocomial Colonization with MDR Pathogens

Age Different underlying diseases Severity of illness Inter-hospital transferred or nursing

home patients Extended length of stay Invasive procedures Anti-infective therapies

Ann Intern Med. 2002;136:834-844

Risk Factors of Nosocomial MRSA Colonization/infection

Advanced age Severity of illness Inter-hosp transfer /nu

rsing home patients Extended length of sta

y GI surgery Central catheter Intubation/ventilator Cephalosporin treated Receiving multiple anti

biotics

Ann Intern Med. 2002;136:834-844

Risks Factors of Nosocomial VRE Colonization/infection Advance age ESRD Hematologic cancer Severity of illness Inter-hosp transfer /nursing ho

me patients Extended length of stay GI surgery Transplantation Central catheter NG tube Cephalosporin treated Clindamycin treated Vancomycin treated Fluoroquinolones treated Receiving multiple antibiotics

Ann Intern Med. 2002;136:834-844

Risks Factors of Nosocomial ESBL-GNB Colonization/infection Severity of illness Inter-hosp transfer /nursing

home patients Extended length of stay GI surgery Central catheter Urinary catheter Intubation/ventilator NG tube Fluoroquinolones treated Receiving multiple antibioti

cs

Ann Intern Med. 2002;136:834-844

Risks Factors of Nosocomial C. difficile Colonization/infection Advance age ESRD Severity of illness Inter-hosp transfer /nursing

home patients Extended length of stay GI surgery Transplantation NG tube Cephalosporin treated Penicillins treated Clindamycin treated Vancomycin treated Receiving multiple antibioti

csAnn Intern Med. 2002;136:834-844

Risks Factors of Nosocomial Candida Colonization/infection Advance age ESRD Hematologic cancer Hepatic failure Inter-hosp transfer /nursing

home patients Extended length of stay GI surgery Transplantation Central catheter Urinary catheter Vancomycin treated Receiving multiple antibioti

cs

Ann Intern Med. 2002;136:834-844

Differences between Hospital- and Community-acquired Infections

Isolates distribution Antimicrobial susceptibility

Eur J Clin Microbiol Infect Dis. 2002;21:849-855

What Has Been Changed in Today’s Community

Spread of drug-resistant bacteria in the community Changing pattern of health care

OPD invasive procedure Hemodialysis clinics Nursing home care

Recently discharged patients

Diversity in Antimicrobial Susceptibility in Community-acquired Bacteremia Isolates

Clin Infect Dis. 2002;34:1431-9

A ： True community-acquired

B ： Recently discharge (30 days)

C ： OPD procedure D ： Nursing home

New Classification-Definition of Healthcare-associated Infection

Hospital-acquired Healthcare-associated (HcA)

Parenteral treatment in 30 days OPD chemotherapy or hemodialysis in 30

days Hospitalization for 2 days in recent 90 da

ys Nursing home residence

Community-acquired (CA)Ann Intern Med. 2002;137:791-797

Healthcare-associated (HcA) Bloodstream Infections HcA infection similar to HA infection in

Comorbidities and predisposing factor Primary site of infection Pathogen pattern and drug-susceptibility Mortality

Clinical importance Empirical antibiotics use Infection control strategy

Ann Intern Med. 2002;137:791-797

Bacteremia in previously Hospitalized community patients

Prospective observational study, NTUH 2001-2002

Antimicrobial-resistant bacteria MRSA Multi-drug resistant Enterobacteriaceae Multi-drug resistant NFGNB

304 community bacteremia patients with previous hospitalization in 360 days

38 (12.5%) with ARB infection Ann Emerg Med. (In revise)

Dilemma in selecting empirical antibiotics

Inappropriate antibiotics Increase mortality in severe sepsis Prolonged hospitalization

Overuse of broad-spectrum antibiotics Emergence of drug-resistant micro-

organism Medical cost

Low antimicrobial resistance in micro-organisms isolated from community patients without healthcare-associated exposure

Diag Microb Infect Dis. 2006;55:135-141

MDR-GNB in the Community

Clin Infect Dis. 2005;40:1792-1780

1998-2003, Boston, USA Increasing prevalence of MDR-GNB

isolates recovered from patients at their initial 48 hours hospitalization

MDR-GNB in the Community

Independent factors for carrying MDR-GNB among community patients

OR 95% CI.

Age ≧ 65 years 2.8 1.1-7.4 Prior Abx ≧ 14 days ＃ 8.7 2.5-30 Long-term care facility P’t 3.5 1.3-9.4

＃ In 90 days prior to this admission

Clin Infect Dis. 2005;40:1792-1780

MRSA in the Community 1997-2002, Boston, USA Increasing carriage percen

tage in community p’t All with HA exposure No CA-MRSA in this study

Independent risk factors

Previous MRSA infection/colonization ＃ (OR, 17)

Cellulitis (OR, 4) Presence of CVC (OR, 3) ＃

Skin ulcer (OR, 3)

＃ In 90 days prior to this admission

J Antimicrob Chemother. 2004;53:474-9.

Susceptibility of S. aureus Bloodstream Isolates in North Taiwan (2001)

Percentage of MRSA bacteremia Without

healthcare-associated exposure: 2.7 % (1/37)

With healthcare-associated exposure : 57.1 % (32/56)

Diag Microb Infect Dis. 2005;53:85-92

Methicillin Resistance among Community-onset S. aureus Bacteremia

2001-2006, NTUH ED, North Taiwan Different HA exposure

Nursing home = 26/29 (90.0 %) OPD invasive procedure = 63/119 (52.9 %) Previously hospitalized = 78/217 (35.9 %)

Antimicrobial-resistant Bacteremia in previously hospitalized patients- Decreased as Duration after Discharge

Ann Emerg Med. (In revise)

Antimicrobial-resistant Bacteremiain Previously Hospitalized Patients

ED, NTUH 304 bacteremia patients

who were previously hospitalized in 360 days

ARB MRSA MDR-GNB

(Enterobacteriaceae, NFGNB)

Risk factors Prior ICU stay in 180

days Prior MRSA carriage in

360 days

Ann Emerg Med. (In revise)

Empirical Antibiotics for Community Patients with Infection- discrimination for healthcare-associated risk

Baseline antimicrobial susceptibility in true community patients

Patients with healthcare-associated risk Nursing home residence Regular OPD invasive procedure in 30 days Recent hospitalization in 90 days

Prior ICU admission Bed-ridden patients Prior prolonged hospitalization > 30 days

Prior carriage of MRSA or multi-drug resistant bacteria in 360 days

Host Factors Consideration

Patient with Impaired Immunity

Advanced age (≧ 65 years) Liver cirrhosis Cancer patients Receiving chemotherapy Alcoholism

Diabetes (?)

Impact of DM on Mortality in Patients with Community-acquired Bacteremia

J Infect. 2007;55:27-33.

ν

νν

νν

ν

ν

Impact of Diabetes on Community-acquired Infections

Higher risk in acquiring infections No survival differences between DM a

nd non-DM patients Community-acquired pneumococcal bac

teremia Community-acquired bacteremia

Early diagnosis > Role of AbxDiabetes Care. 2004;27:1143-7.

Diabetes Care. 2004;27:70-6.

J Infect. 2007;55:27-33.

Impact of Cirrhosis on Mortality in Patients with Community-acquired Bacteremia

0.00

0.20

0.40

0.60

0.80

1.00

Sur

viva

l (pe

rcen

tage

)

0 10 20 30Days since presentation to the ED

No liver cirrhosis Liver cirrhosis

P=<0.001

Clin Infect Dis. In submit.

Primary Site of Infection

Common Primary Site of Infection in Sepsis Patients

Low respiratory tract infection

Lung abscess Genito-urinary tract Intra-abdominal

Hepatobiliary SBP Liver abscess

Soft tissue Necrotizing fasciitis

Orthopedics Endovascular

Infective endocarditis Catheter-related Central venous system Febrile neutropenia Primary bacteremia

Specific Consideration in Taiwan Patient

Liver cirrhosis/HCC Pathogen

K. pneumoniae Vibrio spp. Aeromonas spp

Diseases SBP Biliary tract infection/liver abscess Necrotizing fasciitis

Lung Abscess-High Prevalence of K. pneumoniae in Taiwan

Traditionally focused on anaerobes 1996-2003, NTUH Total 336 cases 120 case with documented bacteriology 90 case were community-acquired

73 (81%) were male 51 (57%) were smoker 33 (37%) with chronic lung disease 28 (31%) with DM

Clin Infect Dis. 2005;40;915-22.

Lung AbscessHigh Prevalence of K. pneumoniae in Taiwan

21 % due to K. pneumoniae Anaerobes and Streptococcus milleri incr

easing resistance to PCN and Clindamyin Recommendation for empirical antibiotics

2° or 3° generation cephalosporin + clindamycin/metronidazole

β-lactam/β-lactam inhibitor

Clin Infect Dis. 2005;40;915-22.

Liver Abscess Highly association with DM

DM history may not present Increasing liver abscess in non-DM patients

Biliary tract enzyme: not usually elevated Easily missed

Fever without apparent focus in ER K. pneumoniae as a predominant pathogen

K. pneumoniae-A Community Pathogen with Low Antimicrobial Resistance

Diag Microb Infect Dis. 2006;55:135-141

What’s the Drug of Choice for Liver Abscess

Retrospective study, 1995-2000, TSGH, Taiwan

107 KP liver abscess Cefazolin: 59 (55.1%) ESCeph: 48 (44.9%)

Optimal Treatment for KP Liver Abscess- Comparison between Extended-Spectrum Cephalosporin (ESCeph) and Cefazolin

Antimocrob Agent Chemother. 2003;47:2088-92.

Optimal Treatment for KP Liver Abscess- Comparison between Extended-Spectrum Cephalosporin and Cefazolin

Metastatic lesions Endophthalmitis Septic pul. embolism Prostatic abscess Renal abscess Epidural abscess Necrotizing fasciitis

Severe complication rate (P<0.001)

Cefazolin: 37.3% ESCeph: 6.3%

Antimocrob Agent Chemother. 2003;47:2088-92.

P = 0.02

P < 0.01

P = 0.42

Optimal Treatment for KP Liver Abscess- Comparison between Extended-Spectrum Cephalosporin and Cefazolin

No difference among the two study groups in

Demographic Comorbidity Severity of acute illness Clinical presentation Early drainage

Combine aminoglycoside (P<0.001)

Cefazolin (50/59, 84.7%) ESCeph (21/48, 43.8%)

Antimocrob Agent Chemother. 2003;47:2088-92.

Optimal Treatment for KP Liver Abscess- Comparison between Extended-Spectrum Cephalosporin and Cefazolin

Factors favoring lower risk of severe complications

OR (95% CI.)Platelet > 100 x 109/liter 0.03 (0.004-0.28)ALP < 300 U/liter 0.19 (0.04-0.78)No gas formation in abscess 0.2 (0.05-0.92)APACHE III score < 40 0.07 (0.01-0.39)Extended-spectrum cephalosporin use ＃ 0.01 (0.001-0.12)Early drainage ＊ 0.11 (0.02-0.53)

＃ For at least 3 days within the first 5 days of hospitalization＊ Within 3 days of diagnosis

Antimocrob Agent Chemother. 2003;47:2088-92.

Rationales for Antimicrobial Agents Selection

1. 可參考的微生物學報告 ____年 ____ 月 ____ 日 ○血液○痰液○尿液○膿液○其它 ________ 菌株 1.______________ 2. ______________ 3.______________

2. 敗血症高死亡率病患 敗血性休克 (收縮壓 :_________mmHg) 嚴重敗血症 (◎lactate≧4 mM ，或◎器官衰竭 ____

腦 ____ 肺 ____ 腎 ____ 肝 ) 中樞神經感染 低中性球發燒 肝膿瘍 壞死性筋膜炎 惡性外耳炎 嚴重肺炎 (◎呼吸窘迫 /衰竭 ◎嚴重度評分大於 90

分 (需附評分表 ) ) 免疫功能低下 (◎年齡大於 70歲 ◎肝硬化併衰竭◎

腫瘤病患 )

3. 具抗藥性細菌感染風險病患 三個月內曾住院 (________________ 醫院 : ____/____/____~____/____/____)

安養中心病患 門診侵入性治療 (◎化療 ◎ H/D ◎TPN ◎其它 :________)

4. 混合型感染 吸入性肺炎 牙源性感染 頸部深部感染 中隔腔炎 腹腔內感染 糖尿病足部病變合併感染

5. 前一線抗生素治療失敗 使用至少超過 48 小時沒有改善 自 ____ 月 ____ 日 ~____ 月 ____ 日使用_______________________ 抗生素

6. 其他特殊臨床考量 請說明選用此抗生素之理由 並照會感染科醫師

Colonization Duration and Risk Factors for Prolonged MRSA Colonization

Estimated half-life of MRSA colonization: 40 months

Detection of MRSA colonization Nares (Sen, 93%; NPV, 95%) Cutaneous sites (Sen, ≦ 39%; NPV ≦ 69%).

Risk factor for prolonged colonization Break in skin (OR. 4.34; 95% CI. 1.6-11.8)

Clin Infect Dis. 1994;19:1123-8.

Clin Infect Dis. 2001;32:1393-8.