ICU獲得性感染

1、Cost of Hospital Stay Associated with ResistanceOrganism/AntibioticUSD (million)MRSE239MRSA122Enterobacter119Ampicillin-resistant E. coli83Imipenem-resistant P. aeruginosa61Vancomycin-resistant Enterococcus37Estimated total costs0.7-1.2 billionOther associated costsSecondary infectionsDays of work l

2、ostPosthospital careOther major costsOverall total estimated costs300 billionValue of A Human Life?Source: OTA Report an overall risk of 18% of acquiring an infection during ICU stay one of the most common causes of death in ICUsEuropean Prevalence of Infection in Intensive Care Study (EPIC) Held on

3、 April 29, 1992 an overall of 9567 patients from 1417 ICUs a total of 45% of patients had an infection ICU-acquired infection21% community-acquired infection14% hospital-acquired infection other than ICU10%InfectionMedicine(%)Surgery(%)ICU(%)LRTI241865UTI433118Soft tissue-1112BSI15102Other183013Noso

4、comial Infection in ICUPredisposing risk factors prolong length of ICU stay antibiotic usage mechanical ventilation urinary catheterization pulmonary artery catheterization central venous access stress ulcer prophylaxis use of steroid nutritional statusNosocomial Infection in ICUDuration of ICU stay

5、 - EPIC datalength of ICU stayOR for NI1 - 2 days13 - 4 days35 - 6 days6 21 days33Nosocomial Infection in ICUUse of Antibiotics - EPIC data of 10,038 patients, 62% received antibiotics for either prophylaxis or treatmentAntibiotics% of pts with abxcephalosporins44broad-spectrum PCN24.3aminoglycoside

6、23.9metronidazole17.1fluoroquinolone11.9glycopeptide11.6Nosocomial Infection in ICUPrevious exposure to antibiotics modify intestinal flora, leading to colonization with resistant bacteria3rd generation cephalosporinsfluoroquinolonesvancomycin favor the selection of inducible beta-lactamase producin

7、g GNB, such as Pseudomonoas aeruginosa, Enterobacter clocae, Serratia spp., and Citrobacter freundiiNosocomial Infection in ICUCommon pathogens community-acquired infection and early ( 4d) hospital-acquired infections Enterobacter spp. Serratia spp. ESBL-producing microorganisms Pseudomonas aerugino

8、sa Acinetobacter spp. MRSA enterococci fungimost common pathogens S. aureus30% P. aeruginosa29% Coagulase-negative staphylococci19% E. coli13% Enterococcus spp.12%Pathogens of nosocomial infection in ICU, PUMCH0%20%40%60%80%100%19951996199719981999Gram-negative bacilliGram-positive rodsFungiOtherGra

9、m-negative pathogens in ICU, PUMCH0%20%40%60%80%100%19951996199719981999AcinetobacterCitrobacterEnte robacterE. ColiKlebsiellaProteusP. AeruginosaStenotrophomonasEmerging PathogensGram-negativebacilli58%Gram-positive rod32%Candida10%Gram-negative bacilliGram-positive rodCandidaData from ICU, PUMCH 1

10、999Emerging PathogensS. aureus28%S.Epidermidis34%Strept.9%E. faecalis23%E. faecium6%S. aureusS. EpidermidisStrept.E. faecalisE. faeciumMechanism of Resistance to Beta-lactam AntibioticsDepartment of Critical Care MedicinePeking Union Medical College HospitalPrinciple of beta-lactam action a rigid ba

11、cterial cell wall protects bacteria from mechanical and osmotic insult beta-lactam inhibits PBPs preventing formation of the peptide bridges producing weakened wall activating cell wall degrading enzymes - autolysin beta-lactam interferes with normal cell wall biosynthesis, causing impaired cellular

12、 function, altered cell morphology or lysisMechanism of Antibiotic ResistanceMechanismExample1. bacterial enzyme production resulting indestruction or structured modification ofantibioticBeta-lactam,macrolide,aminoglycoside2. alteration in bacterial membrane to reduceantibiotic permeabilityQuinolone

13、,aminoglycoside3. alteration in antibiotic target site (e.g.bacterial enzyme of ribosome)Macrolide, quinolonebeta-lactam,aminoglycoside4. modification of bacterial metabolic path-way resulting in bypass of antibiotic site ofinhibitionTrimethoprime,sulphonamide5. promotion of antibiotic efflux from c

14、ell,preventing intracellular accumulation ofantibiotictetracyclineDoes beta-lactamase confer resistance? The amount of enzyme products its ability to hydrolyse the antibiotic in question its interplay with the cellular permeability barriersInducible Beta-lactamase also called class I beta-lactamase

15、or constitutive beta-lactamase or AmpC beta-lactamase most are chromosome-mediated major producers Pseudomonas aeruginosa Enterobacter sp. Citrobacter sp. Serratia sp. Morganella morganniiInducible Beta-lactamase transient elevation in beta-lactamase synthesis when a beta-lactam is present enzyme pr

16、oduction returns to a low level when the inducer is removed low level insufficient to protect bacteria even against drugs rapidly hydrolysed by the enzymes enzyme hyperproducer = mutants that produce Class I enzymes continuously at a high levelInducible Beta-lactamaseStrong inducerWeak inducerLabile

17、1st generation cephalo-sporins, ampicillin, cefo-xitin2nd and 3rd generationcephalosporins, ureido-penicillins, monobactamsStableImipenemtemocillinInduction is lost within 4 to 6 hrs once the strong inducer is removed.Little need for concern if therapy with a strong inducer is discontinued and the d

18、rug replaced by a weak inducer.Activity of Drugs Against Organisms with Elevated Beta-Lactamase Levels Decreased Activity Monobactams Second-, Third-generation cephalosporins Broad-spectrum penicillins Maintain Activity Imipenem, Meropenem Fourth-generation cephalosporins Ciprofloxacin, ofloxacin, e

19、tc SMZ/TMPco (except P. Aeruginosa) AminoglycosidesAntibiogram of Enterobacter19951996199719981999PIP18%23%44%33%5%IMP100%92%100%83%95%CAZ36%31%33%50%21%AMK100%91%88%67%74%CIP82%85%78%45%74%Enterobacter Bacteremia: Clinical Features and Emergence of Antibiotic Resistance during TherapyChow JW, et al

20、Ann Int Med 1991; 115: 585-90Multiresistant EnterobacterM ultiresistantEnterobacter IsolatesAntibiotic*n/N (%)P valueAny antibioticYes36/103 (35)No1/26 (4)0.002Third-generation cephalosporinYes22/32 (69)No14/71 (20)0.001*Antibiotics received in the 2 weeks before the initial positive blood cultureAs

21、sociation of Previously Administered Antibiotics withMultiresistant Enterobacter in the Initial Blood CultureMultiresistant EnterobacterAntibiotic TherapyEmergence of Resistanceto the Therapyn/N (%)Third-generation cephalosporin*6/31 (19)Aminoglycoside*1/89 (1)Other beta-lactam*0/50 (0)Emergence of

22、Resistance to Cephalosporin, Aminoglycoside, and Other Beta-Lactam Therapy* Cefotaxime, ceftazidime, ceftriaxone, ceftizoxime* Gentamicin, tobramicin, amikacin, netilmicin* Imipenem, piperacillin, ticarcillin, aztreonam, mezlocillin, ticarcillin-clavulanateMultiresistant EnterobacterVariab leM o rta

23、lity*P v alu en /N (% )R esistan ceM u ltiresistan t E n tero b acter1 2 /3 7 (3 2 )N o n m u ltiresistan t E n tero b acter1 4 /9 2 (1 5 )0 .0 3S u rg eryR ecen t su rg ery1 7 /5 6 (3 0 )N o recen t su rg ery9 /7 3 (1 2 )0 .0 1T h erap yM o n o th erap y9 /5 4 (1 7 )C o m b in atio n th erap y1 0 /

24、6 4 (1 6 )In ap p ro p riate th erap y7 /11 (6 3 )0 .0 0 1Factors Associated with Mortality in Patients with Enterobacter BacteremiaExtended spectrum beta-lactamase Most are plasmid mediated 1 to 4 amino acid changes from broad-spectrum beta-lactamases, therefore greatly extending substrate range Ma

25、jor producers E. Coli (TEM) Klebsiella sp. (SHV) inhibited by beta-lactamase inhibitorsReliable (relatively) agents for ESBL-producing pathogens Carbapenems Amikacin Cephamycins (except MIR-1 type; 30% of strains) Beta-lactamase inhibitorspip/tazo30% R in Chicago 199626% R in ICU, PUMCH 1999Antibiog

26、ram of E. coli19951996199719981999PIP0%0%55%35%13%IMP94%100%100%95%94%CAZ33%45%91%79%65%AMK83%100%100%89%76%CIP0%8%73%39%29%Antibiogram of Klebsiella19951996199719981999PIP36%12%64%50%8%IMP100%100%100%100%100%CAZ42%19%64%65%42%AMK93%81%100%90%92%CIP64%77%55%65%75%Prevalence of CAZ-R Klebsiella199019

27、93CAZ-R Klebsiella5.2%15.2%Highest in teaching hospitals 500 beds21.8%From Itokazu G, et al. Nationwide Study of Multiresistance Among Gram-Negative Bacilli from ICU patientsClinical Infectious Diseases 1996; 23: 779-85Cross-Resistance inCAZ-R Klebsiella19901993GEN/TOBRA62%73%CIP39.8%51.8%Among CAZ-

28、S Klebsiella both 5%From Itokazu G, et al. Nationwide Study of Multiresistance Among Gram-Negative Bacilli from ICU patientsClinical Infectious Diseases 1996; 23: 779-85Prevalence of ESBLno. of isolatesESBL +veE. coli288 (29%)Klebsiella pneumoniae4019 (48%)Total6827 (40%)Data from Intensive Care Uni

29、t, Peking Union Medical College Hospital, 1999Cross-Resistance inCAZ-R KlebsiellaCAZ-S(n=51)CAZ-R(n=75)GEN27%81%CIP22%36%Data from Intensive Care Unit, Peking Union Medical College Hospital, 1995-1999Effect of ESBL on MortalityESBL +(n=32)ESBL (n=184)P valueMortality of Allpatients46%34%Mortality of

30、 non-ICU patients40%18%0.06Analysis of mortality in 216 bacteremic patients caused by Klebsiella pneumoniaePatterson et al. 37th ICAAC, 1997, Abstr J-210Effect of ESBL on MortalityMortalityP valueS28%-Sensitivity profileR75%0.02IMP23%-Antibiotic usedother42%0.07Patterson et al. 37th ICAAC, 1997, Abs

31、tr J-210Empiric antibiotic therapy in 32 bacteremic patients caused by ESBL-positive Klebsiella pneumoniaeMolecular Epidemiology of CAZ-R E. Coli and K. Pneumoniae Blood IsolatesSchiappa D, et alRush University and University of Illinois, Chicago ILJournal of infectious Diseases 1996; 174: 529-37Ris

32、k Factors for CAZ-RKlebsiella BacteremiaBloodstream IsolatesCharacteristicsCAZ-R(n=31)CAZ-S(n=31)P value95% CINursing Home Resident18 (52)3 (10)0.0009(2.24, 59.38)APACHE II21.8 (8.7)13.1(5.18)0.000001XFoley Catheter25 (81)5 (16)0.000001(5.04, 103.5)G or J Tube14 (45)1 (3)0.0004(3.1, 1076.4)Central V

33、enous Catheter27 (67)11 (36)0.0001(3.01, 58.22)Prior Antibiotics20 (54)8 (26)0.001(2.00, 27.22)CAZ or ATM11 (38)00.009XCAZ-R Klebsiella BacteremiaAppropriateTreatment(N=19)InappropriateTreatment(N=12)Survived18*7Expired15* p = 0.02Outcome of Patients with CAZ-R Bacteremia Who Received Appropriate vs

34、. Inappropriate Therapy Within 72 Hours of Bacteremic EventCeftazidime - emergence of resistance Emergence of Antibiotic-Resistant Pseudomonas aeruginosa: Comparison of Risks Associated with Different Antipseudomonal Agents by Carmeli Y, et al. Antimicrobial Agents and Chemotherapy 1999; 43 (6): 137

35、9-82Ceftazidime - emergence of resistance a 320-bed urban tertiary-care teaching hospital in Boston, Mass. 11,000 admissions per year 4 study agents with antipseudomonal activity ceftazidime, ciprofloxacin, imipenem, piperacillin a total of 271 patients (followed for 3,810 days) with infections due

36、to P. Aeruginosa were treated with the study agents resistance emergence in 28 patients (10.2%), with an incidence of 7.4 per 1,000 patient-daysCeftazidime - emergence of resistanceMultivariable modelAntibioticEvents(no./total Rx)HR (95% CI)P valueCulturing scoreNI2.5 (1.1-6.0)0.04Aminoglycosides13/

37、770.8 (0.4-2.0)0.8Ceftazidime10/1250.7 (0.3-1.7)0.4Ciprofloxacin12/980.8 (0.3-2.0)0.6Imipenem11/372.8 (1.2-6.6)0.02Piperacillin9/911.7 (0.7-4.1)0.3Table. Multivariable Cox hazard models for the emergence of resistance to any of the four study drugsClassification of Antibiotic Therapy Prophylactic Us

38、e Therapeutic Use Empiric therapy Definitive therapyEmpiric Antibiotic TherapyDepartment of Critical Care MedicinePeking Union Medical College HospitalEmpiric Antibiotic Therapy When treating seriously ill patients who are at risk of developing septic shock when pathogens are unknown or not confirme

39、d antibiotic selection according to epidemiology of NI in the ward resistance profile of most common pathogensEmpiric Antibiotic Therapy Searching for infection focus collecting samples for culture starting empiric antibiotic therapy as soon as possible referring to definitive antibiotic therapy as

40、soon as possibleAntibiotic Therapy and Prognosis Objective: To evaluate the relationship between the adequacy of antibiotic treatment for BSI and clinical outcomes among ICU pts Design: Prospective cohort study Setting: A medical ICU (19 beds) and a surgical ICU (18 beds) from a university-affiliate

41、d urban teaching hospital Patients: 492 pts from July 1997 to July 1999 Intervention: NoneAntibiotic Therapy and Prognosis 147 (29.9%) pts received inadequate antimicrobial treatment for their BSI The most commonly identified bloodstream pathogens and their associated rates of inadequate antimicrobi

42、al treatment included vancomycin-resistant enterococci (n = 17; 100%) Candida species (n = 41; 95.1%) MRSA (n = 46; 32.6%) SCoN (n = 96; 21.9%) Pseudomonas aeruginosa (n = 22; 10.0%) Antibiotic Therapy and Prognosis Hospital mortality rate pts with a BSI receiving inadequate antimicrobial tx(61.9%)

43、pts with a BSI receiving adequate antimicrobial tx(28.4%)(RR, 2.18; 95% CI, 1.77 to 2.69; p 0.001) Independent determinant of hospital mortality by multiple logistic regression analysis administration of inadequate antimicrobial tx(OR, 6.86; 95% CI, 5.09 to 9.24; p 0.001)Antibiotic Therapy and Progn

44、osis Independent predictor of the administration of inadequate antimicrobial tx by multiple logistic regression analysis BSI attributed to Candida species(OR, 51.86; 95% CI, 24.57 to 109.49; p 0.001) prior administration of antibiotics during the same hospitalization(OR, 2.08; 95% CI, 1.58 to 2.74;

45、p = 0.008) decreasing serum albumin concentrations (1-g/dL decrements) (OR, 1.37; 95% CI, 1.21 to 1.56; p = 0.014) increasing central catheter duration (1-day increments) (OR, 1.03; 95% CI, 1.02 to 1.04; p = 0.008)Inappropriate empiric antibiotic therapy Objective: to assess the incidence, risk, and

46、 prognosis factors of NP acquired during mechanical ventilation (MV) Settings a 1,000-bed teaching hospital April 1987 through May 1988 Patients 78 (24%) episodes of NP in 322 consecutive mechanically ventilated patientsInappropriate empiric antibiotic therapyOR95% CIP valueThe presence of an ultima

47、tely orrapidly fatal underlying disease8.843.5222.20.0018worsening of acute respiratoryfailure caused by pneumonia11.944.75300.0096the presence of septic shock2.831.415.780.016an inappropriate antibiotic tx5.812.70-12.480.02the type of ICU hospitalization(noncardiac surgerical and non-surgical ICU c

48、ompared withpost-cardiac surgery ICU)3.381.705.710.06From: Torres et al. Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. Am Rev Respir Dis 1990 Sep;142(3):523-8Difficulty in empiric antibiotic therapy Objective: To assess the frequency of and the r

49、easons for changing empiric antibiotics during the treatment of pneumonia acquired in ICU Design: A prospective multicenter study of 1 years duration Setting: Medical and surgical ICUs in 30 hospitals all over Spain. Patients: Of a total of 16,872 patients initially enrolled into the study, 530 pati

50、ents developed 565 episodes of pneumonia after admission to the ICU.Difficulty in empiric antibiotic therapy Empiric antibiotics in 490 (86.7%) of the 565 episodes of pneumonia The most frequently used antibiotics amikacin120 cases tobramycin110 ceftazidime 96 cefotaxime 96 Monotherapy in 135 (27.6%

51、) of the 490 episodes Combination of 2 antibiotics in 306 episodes (62.4%) Combination of 3 antibiotics in 49 episodes (10%)Difficulty in empiric antibiotic therapy The empiric tx modified in 214 (43.7%) cases isolation of a microorganism not covered by treatment133 (62.1%) cases lack of clinical re

52、sponse77 (36%) development of resistance14 (6.6%) Individual factors associated with modification of empiric treatment identified in the multivariate analysis microorganism not covered(RR 22.02; 95%CI 11.54 to 42.60; p 0.0001) administration of more than one antibiotic(RR 1.29; 95% CI 1.02 to 1.65;

53、p = 0.021) previous use of antibiotics(RR 1.22; 95% CI 1.08 to 1.39; p = 0.0018)Difficulty in empiric antibiotic therapy Compared with appropriate empiric therapy, inappropriate therapy was associated with higher mortality (p=0.0385) more complications (p0.001) higher incidence of shock (p 38 C or 1

54、0,000 or 3,000) purulent bronchial secretions Interventions: Bronchoscopy with BAL within 24 h of clinical dx of VAP or progression of an infiltrate due to prior VAP or NP All patients received antibiotics, 107 prior to bronchoscopy and 25 immediately after bronchoscopy.Difficulty in empiric antibio

55、tic therapyAntibiotic therapyPrior tobronchoscopyAfterbronchoscopyAfter BAL dataavailableNone60% (9/15)Adequate38% (6/16)71% (30/42)57% (21/37)Inadequate91% (31/34)70% (16/23)40% (2/5)From: Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C, Matera J, Jolly EC. Impact of BAL data on the therapy an

56、d outcome of ventilator-associated pneumonia. Chest 1997 Mar;111(3):676-85 Difficulty in empiric antibiotic therapyMortality of Patients with Pneumonia Categorized Accordingto Empiric Antibiotic Therapy33.30%60.80%14.30%0%10%20%30%40%50%60%70%appropriate abx(n=51)inappropriate abx(n=51)unnecessary a

57、bx(n=28)MortalityFrom: Kollef MH, Ward S The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator-associated pneumonia. Chest 1998 Feb;113(2):412-20Hospital Infection ControlDepartment of Critical Care MedicinePeking Union Medical College Hospi

58、talScheduled Changes of Empiric Antibiotic Therapy Objective: To determine the impact of a scheduled change of abx classes, used for the empiric tx of suspected gram-negative bacterial infections, on the incidence of VAP and nosocomial bacteremia Patients: 680 patients undergoing cardiac surgery wer

59、e evaluated Intervention: During a 6-mo period (i.e., the before-period), our traditional practice of prescribing a 3rd generation cephalosporin (ceftazidime) for the empiric tx of suspected gram-negative bacterial infections was continued This was followed by a 6-mo period (i.e., the after-period)

60、during which a quinolone (ciprofloxacin) was used in place of the third-generation cephalosporin.Scheduled Changes of Empiric Antibiotic TherapyBefore-period(n=327)After-period(n=353)P valueVAP incidence11.6%6.7%0.028incidence of VAP attributed toabx-resistant G-bacteria4.0%0.9%0.013incidence of bac