1、整理ppt1Dept of Critical Care MedicinePeking Union Medical College Hospital整理ppt2Cost of Hospital Stay Associated with ResistanceOrganism/AntibioticUSD(million)MRSE239MRSA122Enterobacter119Ampicillin-resistant E.coli83Imipenem-resistant P.aeruginosa61Vancomycin-resistant Enterococcus37Estimated total
2、costs0.7-1.2 billionOther associated costsSecondary infectionsDays of work lostPosthospital careOther major costsOverall total estimated costs300 billionValue of A Human Life?Source:OTA Report整理ppt3 an overall risk of 18%of acquiring an infection during ICU stay one of the most common causes of deat
3、h in ICUs整理ppt4European Prevalence of Infection in Intensive Care Study(EPIC)Held on April 29,1992 an overall of 9567 patients from 1417 ICUs整理ppt5 a total of 45%of patients had an infection ICU-acquired infection21%community-acquired infection14%hospital-acquired infection other than ICU10%整理ppt6In
4、fectionMedicine(%)Surgery(%)ICU(%)LRTI241865UTI433118Soft tissue-1112BSI15102Other183013整理ppt7Nosocomial Infection in ICUPredisposing risk factors prolong length of ICU stay antibiotic usage mechanical ventilation urinary catheterization pulmonary artery catheterization central venous access stress
5、ulcer prophylaxis use of steroid nutritional status整理ppt8Nosocomial Infection in ICUDuration of ICU stay-EPIC datalength of ICU stayOR for NI1-2 days13-4 days35-6 days6 21 days33整理ppt9Nosocomial Infection in ICUUse of Antibiotics-EPIC data of 10,038 patients,62%received antibiotics for either prophy
6、laxis 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 1.6整理ppt10Nosocomial Infection in ICUPrevious exposure to antibiotics modify inte
7、stinal 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 clocae,Serratia spp.,and Citrobacter freundii整理ppt11Nosocomial Infection i
8、n ICUCommon pathogens community-acquired infection and early(4d)hospital-acquired infections Enterobacter spp.Serratia spp.ESBL-producing microorganisms Pseudomonas aeruginosa Acinetobacter spp.MRSA enterococci fungi整理ppt13most common pathogens S.aureus30%P.aeruginosa29%Coagulase-negative staphyloco
9、cci19%E.coli13%Enterococcus spp.12%整理ppt14Pathogens of nosocomial infection in ICU,PUMCH0%20%40%60%80%100%19951996199719981999Gram-negative bacilliGram-positive rodsFungiOther整理ppt15Gram-negative pathogens in ICU,PUMCH0%20%40%60%80%100%19951996199719981999AcinetobacterCitrobacterEnte robacterE.ColiK
10、lebsiellaProteusP.AeruginosaStenotrophomonas整理ppt16Emerging PathogensGram-negativebacilli58%Gram-positive rod32%Candida10%Gram-negative bacilliGram-positive rodCandidaData from ICU,PUMCH 1999整理ppt17Emerging PathogensS.aureus28%S.Epidermidis34%Strept.9%E.faecalis23%E.faecium6%S.aureusS.EpidermidisStr
11、ept.E.faecalisE.faecium整理ppt18Mechanism of Resistance to Beta-lactam AntibioticsDepartment of Critical Care MedicinePeking Union Medical College Hospital整理ppt19Principle of beta-lactam action a rigid bacterial cell wall protects bacteria from mechanical and osmotic insult beta-lactam inhibits PBPs p
12、reventing 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 lysis整理ppt20Mechanism of Antibiotic ResistanceMechanismExample1.
13、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)Macrolide,
14、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 ofantibiotictetracycline整理ppt21Does beta-lactamase confer re
15、sistance?The amount of enzyme products its ability to hydrolyse the antibiotic in question its interplay with the cellular permeability barriers整理ppt22Inducible Beta-lactamase also called class I beta-lactamase or constitutive beta-lactamase or AmpC beta-lactamase most are chromosome-mediated major
16、producers Pseudomonas aeruginosa Enterobacter sp.Citrobacter sp.Serratia sp.Morganella morgannii整理ppt23Inducible 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
17、 protect bacteria even against drugs rapidly hydrolysed by the enzymes enzyme hyperproducer=mutants that produce Class I enzymes continuously at a high level整理ppt24Inducible Beta-lactamaseStrong inducerWeak inducerLabile1st generation cephalo-sporins,ampicillin,cefo-xitin2nd and 3rd generationcephal
18、osporins,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 drug replaced by a weak inducer.整理ppt25Activity of Drugs Against Organisms with Eleva
19、ted Beta-Lactamase Levels Decreased ActivityMonobactamsSecond-,Third-generation cephalosporinsBroad-spectrum penicillins Maintain ActivityImipenem,MeropenemFourth-generation cephalosporinsCiprofloxacin,ofloxacin,etcSMZ/TMPco(except P.Aeruginosa)Aminoglycosides整理ppt26Antibiogram of Enterobacter199519
20、96199719981999PIP18%23%44%33%5%IMP100%92%100%83%95%CAZ36%31%33%50%21%AMK100%91%88%67%74%CIP82%85%78%45%74%整理ppt27Enterobacter Bacteremia:Clinical Features and Emergence of Antibiotic Resistance during TherapyChow JW,et alAnn Int Med 1991;115:585-90整理ppt28Multiresistant EnterobacterM ultiresistantEnt
21、erobacter 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 cultureAssociation of Previously Administered Antibiotics withMultiresistant Enterobacte
22、r in the Initial Blood Culture整理ppt29Multiresistant 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 Resistance to Cephalosporin,Aminoglycoside,and Other Beta-Lactam Therapy*Cef
23、otaxime,ceftazidime,ceftriaxone,ceftizoxime*Gentamicin,tobramicin,amikacin,netilmicin*Imipenem,piperacillin,ticarcillin,aztreonam,mezlocillin,ticarcillin-clavulanate整理ppt30Multiresistant 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
24、 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 0/6 4 (1 6)In ap p ro p riate th erap y7/11 (6 3)0.0 0 1Factors Associated with Mortality in Patients
25、with Enterobacter Bacteremia整理ppt31Extended spectrum beta-lactamase 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 inhibitors整理ppt32Reliable(
26、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 1999整理ppt33Antibiogram of E.coli19951996199719981999PIP0%0%55%35%13%IMP94%100%100%95%94%CAZ33%45%91%79%65%AMK83%100%1
27、00%89%76%CIP0%8%73%39%29%整理ppt34Antibiogram 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%整理ppt35Prevalence of CAZ-R Klebsiella19901993CAZ-R Klebsiella5.2%15.2%Highest in teaching hospitals 500 beds21.8%From Itokazu G,
28、et al.Nationwide Study of Multiresistance Among Gram-Negative Bacilli from ICU patientsClinical Infectious Diseases 1996;23:779-85整理ppt36Cross-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
29、 Gram-Negative Bacilli from ICU patientsClinical Infectious Diseases 1996;23:779-85整理ppt37Prevalence of ESBLno.of isolatesESBL+veE.coli288(29%)Klebsiella pneumoniae4019(48%)Total6827(40%)Data from Intensive Care Unit,Peking Union Medical College Hospital,1999整理ppt38Cross-Resistance inCAZ-R Klebsiell
30、aCAZ-S(n=51)CAZ-R(n=75)GEN27%81%CIP22%36%Data from Intensive Care Unit,Peking Union Medical College Hospital,1995-1999整理ppt39Effect 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 c
31、aused by Klebsiella pneumoniaePatterson et al.37th ICAAC,1997,Abstr J-210整理ppt40Effect of ESBL on MortalityMortalityP valueS28%-Sensitivity profileR75%0.02IMP23%-Antibiotic usedother42%0.07Patterson et al.37th ICAAC,1997,Abstr J-210Empiric antibiotic therapy in 32 bacteremic patients caused by ESBL-
32、positive Klebsiella pneumoniae整理ppt41Molecular 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;174:529-37整理ppt42Risk Factors for CAZ-RKlebsiella BacteremiaBloodstream IsolatesCharacte
33、risticsCAZ-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 Venous Catheter27(67)11(36)0.0001(3.01,58.22)Prior Antibiotics20(54)8(26)0.001(2
34、.00,27.22)CAZ or ATM11(38)00.009X整理ppt43CAZ-R Klebsiella BacteremiaAppropriateTreatment(N=19)InappropriateTreatment(N=12)Survived18*7Expired15*p=0.02Outcome of Patients with CAZ-R Bacteremia Who Received Appropriate vs.Inappropriate Therapy Within 72 Hours of Bacteremic Event整理ppt44Ceftazidime-emerg
35、ence 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):1379-82整理ppt45Ceftazidime-emergence of resistance a 320-bed urban tertiary-care teachin
36、g 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 to P.Aeruginosa were treated with the study agents resistance emergence in 28 patients
37、(10.2%),with an incidence of 7.4 per 1,000 patient-days整理ppt46Ceftazidime-emergence of resistanceMultivariable modelAntibioticEvents(no./total Rx)HR(95%CI)P valueCulturing scoreNI2.5(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)0.6Imipe
38、nem11/372.8(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 drugs整理ppt47Classification of Antibiotic Therapy Prophylactic Use Therapeutic Use Empiric therapy Definitive therapy整理ppt48Empiric Antibiotic TherapyD
39、epartment of Critical Care MedicinePeking Union Medical College Hospital整理ppt49Empiric Antibiotic Therapy When treating seriously ill patients who are at risk of developing septic shock when pathogens are unknown or not confirmed antibiotic selection according to epidemiology of NI in the ward resis
40、tance profile of most common pathogens整理ppt50Empiric Antibiotic Therapy Searching for infection focus collecting samples for culture starting empiric antibiotic therapy as soon as possible referring to definitive antibiotic therapy as soon as possible整理ppt51Antibiotic Therapy and Prognosis Objective
41、: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-affiliated urban teaching hospital Patients:492 pts from July 1997 to July
42、 1999 Intervention:None整理ppt52Antibiotic 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 antimicrobial treatment included vancomycin-resistant enterococci(n=17;10
43、0%)Candida species(n=41;95.1%)MRSA(n=46;32.6%)SCoN(n=96;21.9%)Pseudomonas aeruginosa(n=22;10.0%)整理ppt53Antibiotic Therapy and Prognosis Hospital mortality rate pts with a BSI receiving inadequate antimicrobial tx(61.9%)pts with a BSI receiving adequate antimicrobial tx(28.4%)(RR,2.18;95%CI,1.77 to 2
44、.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)整理ppt54Antibiotic Therapy and PrognosisIndependent predictor of the administration of inadequate antimicrobial tx by mul
45、tiple 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 albumin concentrations(1-g/dL decrements)(OR,1.37;95%CI,1.21 to 1.56;p=0
46、.014)increasing central catheter duration(1-day increments)(OR,1.03;95%CI,1.02 to 1.04;p=0.008)整理ppt55Inappropriate empiric antibiotic therapy Objective:to assess the incidence,risk,and prognosis factors of NP acquired during mechanical ventilation(MV)Settings a 1,000-bed teaching hospital April 198
47、7 through May 1988 Patients 78(24%)episodes of NP in 322 consecutive mechanically ventilated patients整理ppt56Inappropriate empiric antibiotic therapyOR95%CIP valueThe presence of an ultimately orrapidly fatal underlying disease8.843.5222.20.0018worsening of acute respiratoryfailure caused by pneumoni
48、a11.944.75300.0096the 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)3.381.705.710.06From:Torres et al.Incidence,risk,and prognosis factors of no
49、socomial pneumonia in mechanically ventilated patients.Am Rev Respir Dis 1990 Sep;142(3):523-8整理ppt57Difficulty in empiric antibiotic therapy Objective:To assess the frequency of and the reasons for changing empiric antibiotics during the treatment of pneumonia acquired in ICU Design:A prospective m
50、ulticenter 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.整理ppt58Difficulty in empiric antibiotic therapy E
