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1、Dept of Critical Care MedicinePeking Union Medical College Hospital,ICU-acquired Infection and Strategy of Antibiotic Therapy,Cost of Hospital Stay Associated with Resistance,Nosocomial Infection in ICU,an overall risk of 18%of acquiring an infection during ICU stayone of the most common causes of d
2、eath in ICUs,Nosocomial Infection in ICU,European Prevalence of Infection in Intensive Care Study(EPIC)Held on April 29,1992an overall of 9567 patientsfrom 1417 ICUs,EPIC Data,a total of 45%of patients had an infectionICU-acquired infection21%community-acquired infection14%hospital-acquired infectio
3、n other than ICU10%,Nosocomial InfectionVincent et al.JAMA 1995;374:639-644(EPIC),Nosocomial Infection in ICU,Predisposing risk factors,prolong length of ICU stayantibiotic usagemechanical ventilationurinary catheterization,pulmonary artery catheterizationcentral venous accessstress ulcer prophylaxi
4、suse of steroidnutritional status,Nosocomial Infection in ICU,Nosocomial Infection in ICU,Use of Antibiotics-EPIC dataof 10,038 patients,62%received antibiotics for either prophylaxis or treatment,Nosocomial Infection in ICU,Previous exposure to antibioticsmodify intestinal flora,leading to coloniza
5、tion with resistant bacteria3rd generation cephalosporinsfluoroquinolonesvancomycinfavor the selection of inducible beta-lactamase producing GNB,such as Pseudomonoas aeruginosa,Enterobacter clocae,Serratia spp.,and Citrobacter freundii,Nosocomial Infection in ICU,Common pathogens community-acquired
6、infection and early(4d)hospital-acquired infectionsStreptococcus pneumoniaeHaemophilus influenzaeEnterobacteriaceae(Escherichia coli,Proteus spp.,Klebsiella pneumoniae)MSSAStreptococcianaerobes,Nosocomial Infection in ICU,Common pathogens late(4d)hospital-acquired infectionsEnterobacter spp.Serratia
7、 spp.ESBL-producing microorganismsPseudomonas aeruginosaAcinetobacter spp.MRSAenterococcifungi,EPIC Data,most common pathogensS.aureus30%P.aeruginosa29%Coagulase-negative staphylococci19%E.coli13%Enterococcus spp.12%,Emerging Pathogens,Data from ICU,PUMCH 1999,Emerging Pathogens,Mechanism of Resista
8、nce to Beta-lactam Antibiotics,Department of Critical Care MedicinePeking Union Medical College Hospital,Principle of beta-lactam action,a rigid bacterial cell wall protects bacteria from mechanical and osmotic insultbeta-lactam inhibits PBPspreventing formation of the peptide bridgesproducing weake
9、ned wallactivating cell wall degrading enzymes-autolysinbeta-lactam interferes with normal cell wall biosynthesis,causing impaired cellular function,altered cell morphology or lysis,Mechanism of Antibiotic Resistance,Does beta-lactamase confer resistance?,The amount of enzyme productsits ability to
10、hydrolyse the antibiotic in questionits interplay with the cellular permeability barriers,Inducible Beta-lactamase,also called class I beta-lactamase or constitutive beta-lactamase or AmpC beta-lactamasemost are chromosome-mediatedmajor producersPseudomonas aeruginosaEnterobacter sp.Citrobacter sp.S
11、erratia sp.Morganella morgannii,Inducible Beta-lactamase,transient elevation in beta-lactamase synthesis when a beta-lactam is presentenzyme production returns to a low level when the inducer is removedlow level insufficient to protect bacteria even against drugs rapidly hydrolysed by the enzymesenz
12、yme hyperproducer=mutants that produce Class I enzymes continuously at a high level,Inducible Beta-lactamase,Induction 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.,Activi
13、ty of Drugs Against Organisms with Elevated Beta-Lactamase Levels,Decreased ActivityMonobactamsSecond-,Third-generation cephalosporinsBroad-spectrum penicillinsMaintain ActivityImipenem,MeropenemFourth-generation cephalosporinsCiprofloxacin,ofloxacin,etcSMZ/TMPco(except P.Aeruginosa)Aminoglycosides,
14、Antibiogram of Enterobacter,Enterobacter Bacteremia:Clinical Features and Emergence of Antibiotic Resistance during Therapy,Chow JW,et alAnn Int Med 1991;115:585-90,Multiresistant Enterobacter,*Antibiotics received in the 2 weeks before the initial positive blood culture,Association of Previously Ad
15、ministered Antibiotics withMultiresistant Enterobacter in the Initial Blood Culture,Multiresistant Enterobacter,Emergence of Resistance to Cephalosporin,Aminoglycoside,and Other Beta-Lactam Therapy,*Cefotaxime,ceftazidime,ceftriaxone,ceftizoxime*Gentamicin,tobramicin,amikacin,netilmicin*Imipenem,pip
16、eracillin,ticarcillin,aztreonam,mezlocillin,ticarcillin-clavulanate,Multiresistant Enterobacter,Factors Associated with Mortality in Patients with Enterobacter Bacteremia,Extended spectrum beta-lactamase,Most are plasmid mediated1 to 4 amino acid changes from broad-spectrum beta-lactamases,therefore
17、 greatly extending substrate rangeMajor producersE.Coli(TEM)Klebsiella sp.(SHV)inhibited by beta-lactamase inhibitors,Reliable(relatively)agents for ESBL-producing pathogens,CarbapenemsAmikacinCephamycins(except MIR-1 type;30%of strains)Beta-lactamase inhibitorspip/tazo30%R in Chicago 199626%R in IC
18、U,PUMCH 1999,Antibiogram of E.coli,Antibiogram of Klebsiella,Prevalence of CAZ-R Klebsiella,From Itokazu G,et al.Nationwide Study of Multiresistance Among Gram-Negative Bacilli from ICU patientsClinical Infectious Diseases 1996;23:779-85,Cross-Resistance inCAZ-R Klebsiella,From Itokazu G,et al.Natio
19、nwide Study of Multiresistance Among Gram-Negative Bacilli from ICU patientsClinical Infectious Diseases 1996;23:779-85,Prevalence of ESBL,Data from Intensive Care Unit,Peking Union Medical College Hospital,1999,Cross-Resistance inCAZ-R Klebsiella,Data from Intensive Care Unit,Peking Union Medical C
20、ollege Hospital,1995-1999,Effect of ESBL on Mortality,Analysis of mortality in 216 bacteremic patients caused by Klebsiella pneumoniae,Patterson et al.37th ICAAC,1997,Abstr J-210,Effect of ESBL on Mortality,Patterson et al.37th ICAAC,1997,Abstr J-210,Empiric antibiotic therapy in 32 bacteremic patie
21、nts caused by ESBL-positive Klebsiella pneumoniae,Molecular Epidemiology of CAZ-R E.Coli and K.Pneumoniae Blood Isolates,Schiappa D,et alRush University and University of Illinois,Chicago ILJournal of infectious Diseases 1996;174:529-37,Risk Factors for CAZ-RKlebsiella Bacteremia,CAZ-R Klebsiella Ba
22、cteremia,*p=0.02,Outcome of Patients with CAZ-R Bacteremia Who Received Appropriate vs.Inappropriate Therapy Within 72 Hours of Bacteremic Event,Ceftazidime-emergence of resistance,Emergence of Antibiotic-Resistant Pseudomonas aeruginosa:Comparison of Risks Associated with Different Antipseudomonal
23、Agentsby Carmeli Y,et al.Antimicrobial Agents and Chemotherapy 1999;43(6):1379-82,Ceftazidime-emergence of resistance,a 320-bed urban tertiary-care teaching hospital in Boston,Mass.11,000 admissions per year4 study agents with antipseudomonal activityceftazidime,ciprofloxacin,imipenem,piperacillina
24、total of 271 patients(followed for 3,810 days)with infections due to P.Aeruginosa were treated with the study agentsresistance emergence in 28 patients(10.2%),with an incidence of 7.4 per 1,000 patient-days,Ceftazidime-emergence of resistance,Table.Multivariable Cox hazard models for the emergence o
25、f resistance to any of the four study drugs,Classification of Antibiotic Therapy,Prophylactic UseTherapeutic UseEmpiric therapyDefinitive therapy,Empiric Antibiotic Therapy,Department of Critical Care MedicinePeking Union Medical College Hospital,Empiric Antibiotic Therapy,When treating seriously il
26、l patients who are at risk of developing septic shockwhen pathogens are unknown or not confirmedantibiotic selection according toepidemiology of NI in the wardresistance profile of most common pathogens,Empiric Antibiotic Therapy,Searching for infection focuscollecting samples for culturestarting em
27、piric antibiotic therapy as soon as possiblereferring to definitive antibiotic therapy as soon as possible,Antibiotic Therapy and Prognosis,Objective:To evaluate the relationship between the adequacy of antibiotic treatment for BSI and clinical outcomes among ICU ptsDesign:Prospective cohort studySe
28、tting:A medical ICU(19 beds)and a surgical ICU(18 beds)from a university-affiliated urban teaching hospitalPatients:492 pts from July 1997 to July 1999Intervention:None,Antibiotic Therapy and Prognosis,147(29.9%)pts received inadequate antimicrobial treatment for their BSIThe most commonly identifie
29、d bloodstream pathogens and their associated rates of inadequate antimicrobial treatment includedvancomycin-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 ratepts with a
30、 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 2.69;p 0.001)Independent determinant of hospital mortality by multiple logistic regression analysisadministration of inadequate antimicrobial tx(OR,6.86;95%CI,5.09 to 9.24
31、;p 0.001),Antibiotic Therapy and Prognosis,Independent predictor of the administration of inadequate antimicrobial tx by multiple logistic regression analysisBSI 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(O
32、R,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=0.014)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,a
33、nd prognosis factors of NP acquired during mechanical ventilation(MV)Settingsa 1,000-bed teaching hospitalApril 1987 through May 1988Patients78(24%)episodes of NP in 322 consecutive mechanically ventilated patients,Inappropriate empiric antibiotic therapy,From:Torres et al.Incidence,risk,and prognos
34、is factors of nosocomial pneumonia in mechanically ventilated patients.Am Rev Respir Dis 1990 Sep;142(3):523-8,Difficulty in empiric antibiotic therapy,Objective:To assess the frequency of and the reasons for changing empiric antibiotics during the treatment of pneumonia acquired in ICUDesign:A pros
35、pective multicenter study of 1 years durationSetting: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.,Difficulty in empiric antibiotic therapy
36、,Empiric antibiotics in 490(86.7%)of the 565 episodes of pneumoniaThe most frequently used antibioticsamikacin120 casestobramycin110ceftazidime 96cefotaxime 96Monotherapy in 135(27.6%)of the 490 episodesCombination of 2 antibiotics in 306 episodes(62.4%)Combination of 3 antibiotics in 49 episodes(10
37、%),Difficulty in empiric antibiotic therapy,The empiric tx modified in 214(43.7%)casesisolation of a microorganism not covered by treatment133(62.1%)caseslack of clinical response77(36%)development of resistance14(6.6%)Individual factors associated with modification of empiric treatment identified i
38、n the multivariate analysismicroorganism 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 empiric antibiotic therapy,Compared with appropriat
39、e empiric therapy,inappropriate therapy was associated withhigher mortality(p=0.0385)more complications(p0.001)higher incidence of shock(p0.005)more GIB(p=0.003),From:Alvarez-Lerma F.Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit.ICU-Acqui
40、red Pneumonia Study Group.Intensive Care Med 1996 May;22(5):387-94,Difficulty in empiric antibiotic therapy,ObjectiveTo define the impact of BAL data on the selection of antibiotics and the outcomes of patients with VAPDesign:Prospective observation and bronchoscopy with BAL,performed within 24 h of
41、 dx of a new episode of hospital-acquired VAP or progression of a prior episode of NPSetting:A 15-bed medical and surgical ICU,Difficulty in empiric antibiotic therapy,Patients:132 pts hospitalized for more than 72 hmechanically ventilateda new or progressive lung infiltrate plus at least two of the
42、 following three clinical criteria for VAPabnormal temperature(38 C or 10,000 or 3,000)purulent bronchial secretionsInterventions:Bronchoscopy with BAL within 24 h of clinical dx of VAP or progression of an infiltrate due to prior VAP or NPAll patients received antibiotics,107 prior to bronchoscopy
43、and 25 immediately after bronchoscopy.,Difficulty in empiric antibiotic therapy,From:Luna CM,Vujacich P,Niederman MS,Vay C,Gherardi C,Matera J,Jolly EC.Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia.Chest 1997 Mar;111(3):676-85,Difficulty in empiric antibiotic thera
44、py,From: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):412-20,Hospital Infection Control,Department of Critical Care MedicinePeking Union Medical College Hospital,Scheduled Ch
45、anges 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 bacteremiaPatients:680 patients undergoing cardiac surgery were evaluatedIntervent
46、ion: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 continuedThis was followed by a 6-mo period(i.e.,the after-period)during which a quinolone(ciprof
47、loxacin)was used in place of the third-generation cephalosporin.,Scheduled Changes of Empiric Antibiotic Therapy,From:Kollef MH,Vlasnik J,Sharpless L,Pasque C,Murphy D,Fraser V Scheduled change of antibiotic classes:a strategy to decrease the incidence of ventilator-associated pneumonia.Am J Respir
48、Crit Care Med 1997 Oct;156(4 Pt 1):1040-8,Nosocomial Infection Control,Scheduled changes of antibiotic classes for empiric treatment of suspected or documented GNB infectionsTime period 1(n=1323)ceftazidimeTime period 2(n=1243)ciprofloxacinTime period 3(n=1102)cefepime,Nosocomial Infection Control,S
49、cheduled changes of antibiotic classes targeted at the empiric treatment of gram-negative bacterial infections can reduce the occurrence of inadequate antimicrobial treatment of nosocomial infectionsreducing the administration of inadequate antimicrobial treatment for patients with an APACHE II 15 c
50、an improve hospital survival,From Kollef MH.The clinical impact of scheduled antibiotic class changes for the empiric treatment of nosocomial gram-negative bacterial infections in the intensive care unit(ICU)setting.Abstracts of 39th ICAAC 1999:594,Evaluation of Clinical Practice Guidelines on Outco
