1、ICU获得性感染获得性感染 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 April 29,1992 an overall of 9567 patients from 1417 ICUs a total of 45%of patients had an infection ICU-ac
2、quired infection21%community-acquired infection14%hospital-acquired infection other than ICU10%InfectionMedicine(%)Surgery(%)ICU(%)LRTI241865UTI433118Soft tissue-1112BSI15102Other183013Nosocomial Infection in ICUPredisposing risk factors prolong length of ICU stay antibiotic usage mechanical ventila
3、tion urinary catheterization pulmonary artery catheterization central venous access stress ulcer prophylaxis use of steroid nutritional statusNosocomial Infection in ICUDuration of ICU stay-EPIC datalength of ICU stayOR for NI1-2 days13-4 days35-6 days6 21 days33Nosocomial Infection in ICUUse of Ant
4、ibiotics-EPIC data of 10,038 patients,62%received antibiotics for either prophylaxis or treatmentA n tib io tic s%o f p ts w ith a b xc e p h a lo s p o rin s4 4b ro a d-s p e c tru m P C N2 4.3a m in o g lyc o s id e2 3.9m e tro n id a z o le1 7.1flu o ro q u in o lo n e1 1.9g lyc o p e p tid e1 1.
5、6Nosocomial Infection in ICUPrevious exposure to antibiotics modify intestinal flora,leading to colonization with resistant bacteria 3rd generation cephalosporins fluoroquinolones vancomycin favor the selection of inducible beta-lactamase producing GNB,such as Pseudomonoas aeruginosa,Enterobacter cl
6、ocae,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 aeruginosa Acinetobacter spp.MRSA enterococci fungimost common pathoge
7、ns 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 rodsFungiOtherGram-negative pathogens in ICU,PUMCH0%20%40%60%80%100%19951996199719981999
8、AcinetobacterCitrobacterEnte robacterE.ColiKlebsiellaProteusP.AeruginosaStenotrophomonasEmerging PathogensGram-negativebacilli58%Gram-positive rod32%Candida10%Gram-negative bacilliGram-positive rodCandidaData from ICU,PUMCH 1999Emerging PathogensS.aureus28%S.Epidermidis34%Strept.9%E.faecalis23%E.fae
9、cium6%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 bacterial cell wall protects bacteria from mechanical and osmotic insult beta-lactam
10、 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 function,altered cell morphology or lysisMechanism of Antibiotic ResistanceMechanism
11、Example1.bacterial enzyme production resulting indestruction or structured modification ofantibioticBeta-lactam,macrolide,aminoglycoside2.alteration in bacterial membrane to reduceantibiotic permeabilityQuinolone,aminoglycoside3.alteration in antibiotic target site(e.g.bacterial enzyme of ribosome)M
12、acrolide,quinolonebeta-lactam,aminoglycoside4.modification of bacterial metabolic path-way resulting in bypass of antibiotic site ofinhibitionTrimethoprime,sulphonamide5.promotion of antibiotic efflux from cell,preventing intracellular accumulation ofantibiotictetracyclineDoes beta-lactamase confer
13、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 or constitutive beta-lactamase or AmpC beta-lactamase most are chromosome-mediated major produ
14、cers 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 production returns to a low level when the inducer is removed low level insufficient to protect bac
15、teria even against drugs rapidly hydrolysed by the enzymes enzyme hyperproducer=mutants that produce Class I enzymes continuously at a high levelInducible Beta-lactamaseStrong inducerWeak inducerLabile1st generation cephalo-sporins,ampicillin,cefo-xitin2nd and 3rd generationcephalosporins,ureido-pen
16、icillins,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 drug replaced by a weak inducer.Activity of Drugs Against Organisms with Elevated Beta-Lactamase Levels
17、Decreased ActivityMonobactamsSecond-,Third-generation cephalosporinsBroad-spectrum penicillins Maintain ActivityImipenem,MeropenemFourth-generation cephalosporinsCiprofloxacin,ofloxacin,etcSMZ/TMPco(except P.Aeruginosa)AminoglycosidesAntibiogram of Enterobacter19951996199719981999PIP18%23%44%33%5%IM
18、P100%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 alAnn Int Med 1991;115:585-90Multiresistant EnterobacterM ultiresistantEnterobacter IsolatesAntibiotic*n/N(%)P valueAny a
19、ntibioticYes36/103(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 cultureAssociation of Previously Administered Antibiotics withMultiresistant Enterobacter in the Initial Blood CultureMultiresistant En
20、terobacterAntibiotic TherapyEmergence of Resistanceto the Therapyn/N(%)Third-generation cephalosporin*6/31(19)Aminoglycoside*1/89(1)Other beta-lactam*0/50(0)Emergence of Resistance to Cephalosporin,Aminoglycoside,and Other Beta-Lactam Therapy*Cefotaxime,ceftazidime,ceftriaxone,ceftizoxime*Gentamicin
21、,tobramicin,amikacin,netilmicin*Imipenem,piperacillin,ticarcillin,aztreonam,mezlocillin,ticarcillin-clavulanateMultiresistant EnterobacterVariab leM o rtality*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 e
22、ryR 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 0/6 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
23、Most are plasmid mediated 1 to 4 amino acid changes from broad-spectrum beta-lactamases,therefore greatly extending substrate range Major producers E.Coli(TEM)Klebsiella sp.(SHV)inhibited by beta-lactamase inhibitorsReliable(relatively)agents for ESBL-producing pathogens Carbapenems Amikacin Cephamy
24、cins(except MIR-1 type;30%of strains)Beta-lactamase inhibitorspip/tazo30%R in Chicago 199626%R in ICU,PUMCH 1999Antibiogram 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%
25、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 Klebsiella19901993CAZ-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
26、Infectious Diseases 1996;23:779-85Cross-Resistance inCAZ-R Klebsiella19901993GEN/TOBRA62%73%CIP39.8%51.8%Among CAZ-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
27、.of isolatesESBL+veE.coli288(29%)Klebsiella pneumoniae4019(48%)Total6827(40%)Data from Intensive Care Unit,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,1995-199
28、9Effect of ESBL on MortalityESBL+(n=32)ESBL(n=184)P valueMortality of Allpatients46%34%Mortality of 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%-Sen
29、sitivity profileR75%0.02IMP23%-Antibiotic usedother42%0.07Patterson et al.37th ICAAC,1997,Abstr 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
30、 and University of Illinois,Chicago ILJournal of infectious Diseases 1996;174:529-37Risk 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(
31、81)5(16)0.000001(5.04,103.5)G or J Tube14(45)1(3)0.0004(3.1,1076.4)Central Venous 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=0.02Out
32、come of Patients with CAZ-R Bacteremia Who Received Appropriate vs.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,e
33、t al.Antimicrobial Agents and Chemotherapy 1999;43(6):1379-82Ceftazidime-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 patie
34、nts(followed for 3,810 days)with infections due 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 s
35、coreNI2.5(1.1-6.0)0.04Aminoglycosides13/770.8(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
36、Antibiotic Therapy Prophylactic Use 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 pat
37、hogens are unknown or not confirmed 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
38、 definitive antibiotic therapy as 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)
39、from a university-affiliated 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
40、 inadequate antimicrobial 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%)pts
41、 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 PrognosisIndependen
42、t 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;p=0.008)decreasing serum a
43、lbumin 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 prognosis factors of NP acquired during mechanical
44、 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 ultimately orrapidly fatal underlying disease8.843.5222.20.001
45、8worsening 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 compared withpost-cardiac surgery ICU)3.381.705.710.06Fro
46、m: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 reasons for changing empiric antibiotics during the treatment o
47、f 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 patients developed 565 episodes of pneumonia after admission to the ICU
48、.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%)of the 490 episodes Combination of 2 antibiotics in 306 episodes(62.4
49、%)Combination of 3 antibiotics in 49 episodes(10%)Difficulty in empiric antibiotic therapyThe empiric tx modified in 214(43.7%)cases isolation of a microorganism not covered by treatment133(62.1%)cases lack of clinical response77(36%)development of resistance14(6.6%)Individual factors associated wit
50、h 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;p=0.021)previous use of antibiotics(RR 1.22;95%CI 1.08 to 1.39;p=0.0018)Difficulty in emp
