1、How to select antimicrobials?Carlos A.DiazGranados,MD,MSPrinciple of Antibiotic Therapy#1-Is there an infectious syndrome?Is an antibiotic indicated?Common situations where antimicrobials are used unnecessarily Treatment of asymptomatic bacteriuria or funguria 100%with chronic foley have bacteriuria
2、 Only Pregnant woman and persons undergoing urologic procedures should even be screened*Rx.of contaminant blood cultures Endotracheal colonization Noninfectious causes of fever Decubitus Ulcers Viral infections*IDSA Guideline on Assymptomatic Bacteruria.Clin Infect Dis.2005 Mar 1;40(5):643-54.Lets a
3、ssume that an antibiotic is indicated Decision makingImportant criteria for decision making Antimicrobial efficacy Antimicrobial toxicity Presumptive ecologic impact(antibiotic pressure to select or favor emergence of resistance)Narrow vs.broad?Antimicrobial costAntimicrobial efficacy Expected micro
4、biology Probability of antimicrobial resistance of the suspected organism/organisms.Pharmacokinetics/Pharmacodynamics of antimicrobial options-site of infection,etc Patients severity of illnessAntimicrobial Agents:Overriding Premise for Use Because of the potential to develop resistance,antimicrobia
5、ls are fundamentally different from all other classes of pharmacotherapy Antimicrobials should be viewed as medical treasures and a preciousresourceAntibiotics as“Common property resources”“Externality”:the use of an antibiotic by one person can affect others without their permission.Providing antib
6、iotic to one patient today will affect the possibility of providing that antibiotic to someone else in the future(because antibiotic use leads to resistance to that antibiotic).Scott RD,Solomon SL,McGowan JE.Emerging Infectious Diseases 2001;7:282.Analogy-Fishery Only one fish stock with a limited n
7、umber of fish.Many fishermen.A fisherman can overfish and diminish the future stock of fish for all other fishermen of the same fish stock.Components of Appropriate Antimicrobial Use Appropriate selection(usually empiric)Appropriate dosing and route Appropriate de-escalation or streamlining(adjustin
8、g antibiotic according to microbiology results).Appropriate duration.The Continuum of Appropriate Antimicrobial UseAppropriate selection(usually empiric)Use guidelines,preferably local.Use local data preferably.Appropriate selection(usually empiric)Evaluate risk factors for resistant gram-negative o
9、rganisms-categories:No risk factors Risk factors for resistant organisms Risk factors for multi-drug resistant organisms.Risk factors for Imipenem-resistant organisms.If patient does not have risk factors for resistant organisms,then DO NOT use broad spectrum agents(i.e.Zosyn,Imipenem).Resistance-In
10、duced Antimicrobial Substitution Resistant infections require the use of an alternative antimicrobial,usually more toxic,more expensive and with broader antimicrobial spectrum.Once the frequency of resistance to the initially preferred antimicrobial crosses certain threshold level in the community o
11、r the hospital,physicians will start using the alternative antimicrobial more frequently than the one initially preferred.Resistance-Induced Antimicrobial Substitution Consequence of physicians trying to maximize the chances of administering an active empiric antibiotic to an infected patient when t
12、he antimicrobial susceptibility of the infecting organism is unknown.This switch is done in patients with a variety of infectious syndromes for which the resistant microbe is considered likely and not only for patients that are actually infected with the resistant microbe.Association between severit
13、y of illness and threshold for antimicrobial substitution Scenario#1:Patient with low grade fevers,mild tachycardia,WBC 12k,normal mental status,no comorbid illnesses,received Ceftriaxone for several days 3 weeks ago for presumtive DGI(hospital stay was 4 days).No other previous hospital stay.Scenar
14、io#2:recently diagnosed HIV/AIDS,CD4=2,fever of 40.1,hypotension requiring pressors,received Ceftriaxone for several days 3 weeks ago for presumptive CAP(hospital stay was 4 days).No other previous hospital stay.The Role of Severity of IllnessAre active empiric antimicrobials important for patient o
15、utcomes?Are active empiric antimicrobials important for patient outcomes?Are active empiric antimicrobials important for patient outcomes?Are active empiric antimicrobials important for patient outcomes?Are active empiric antimicrobials important for patient outcomes?Severity of illness may be a MOD
16、IFIER of the effect of active empiric antimicrobial on patient outcome Patients that are not too ill may do OK even if an active empiric antimicrobial is delayed.Patients that are significantly ill but NOT extremely ill may have better outcomes if an active empiric antimicrobial is given.Patients th
17、at are extremely ill will likely die regardless of whether an active empiric antimicrobial is given or not.Severity of illness A modifier of the effect of optimal antimicrobials on outcome?Severity of illness A modifier of the effect of optimal antimicrobials on outcome?Severity of illness A modifie
18、r of the effect of optimal antimicrobials on outcome?Severity of illness A modifier of the effect of optimal antimicrobials on outcome?My conclusion re:severity of illness and antibiotic selection Balance risk of resistance and severity of infectious syndrome when selecting an empiric antimicrobial.
19、Patient not too ill-be more conservative.Patient severely ill-be more aggressiveIndications for Empiric Zosyn use in patients with Community-Acquired Infections Limb or life threatening diabetic foot infections(open skin and soft tissue infection)Close cellulitis usually does not required Pseudomona
20、s coverage.CAP with structural airway disease(i.e.bronchiectasis).?Severe intrabdominal infections in patients admitted to the ICU.Neutropenic feverOther Risk factors for resistant pathogens Consider empiric Zosyn or alike(Usually in combination with Vancomycin and either a Quinolone or an Aminoglyc
21、oside).Current hospitalization 2 days.Recent hospitalization for 4 days in last 90 days.Residence in Nursing Home or long term care facility(LTAC)for at least 4 days in last 90 days Received 3 days of antibiotics in last 90 daysIn the last 30 days received:Home infusion therapy Home wound care Hemod
22、ialysisEmpiric Combination Therapy for Pseudomonal Bacteremia Improves Survival30 day survival,N=115AAC 2003;47:2756Consider Rx for Multi-drug resistant organisms(i.e.consider using Imipenem)if:Apache II 15 or On pressors 10 hospital days or 3 ICU daysIn the last 30 days 3 days of:-3er gen.cephalosp
23、orines -Quinolones -Piperacillin-tazobactamIn the last 30 days 3 days of:-3er gen.cephalosporines -Quinolones -Piperacillin-tazobactamIn the last 10 daysOR/ANDANDIn search of a consensusDefinitions!Piperacillin/tazobactam-requiring organism:A microorganism that is susceptible to piperacillin-tazobac
24、tam but resistant to ampicillin,first generation cephalosporins,ceftriaxone and quinolones(and aminoglycosides for urine cultures if the patient doesnt have high risk of renal failure).Pseudomonas aeruginosa.Imipenem-requiring organism:An enterobacteriaceae producing extended-spectrum betalactamases
25、(ESBL)-?-Serratia spp.,Providencia spp.,Citrobacter spp.,Enterobacter spp.resistant to quinolones.A microorganism other than the above that is susceptible to imipenem but resistant to ampicillin,first generation cephalosporins,ceftriaxone,ceftazidime,quinolones,and piperacillin-tazobactam(and aminog
26、lycosides for urine cultures if the patient doesnt have a high risk of renal disease).Type of Empiric AntimicrobialVariableOverallN=194ImipenemN=66Pip-tazoN=128p-valueVancomycin148(76%)53(80%)95(74%)0.34Levofloxacin31(16%)2(3%)29(23%)0.0004Amikacin55(28%)54(82%)1(1%)15134(69%)42(64%)92(72%)0.25Grady
27、 AUP,unpublishedPredictors of Imipenem-requiring organisms(IRO)in the ICUCross-sectional study of 279 patients in the ICU(MICU or SICU teams only)with suspected gram-negative infections.Overall frequency of Imipenem-Requiring organism was 3.9%(11/279).Imipenem was the empiric antimicrobial prescribe
28、d to 33%of the patients.Bivariate analyses and multivariate logistic regression analysis used to evaluate predictors of IRO.Grady AUP,unpublishedPredictors of Imipenem-requiring organisms(IRO)in the ICU Bivariate analyses:Preceding length of hospital stay(p=0.0004)Preceding ICU(p=0.03)stay Duration
29、of previous antibiotic(p=0.0002)Previous Piperacillin-Tazobactam Rx(p=0.006)Being care for by the surgical ICU team(p=0.04).Multivariate analysis:Duration of previous antibiotic(p=0.025).IRO-Predictors studyGrady AUP,unpublishedImipenem-resistant organisms in the hospitalized patient with sepsisSome
30、 Pseudomonas aeruginosaSome Acinetobacter spp.Xanthomonas maltophiliaBurkholderia cepaciaKPC Klebsiella spp.KPC E.coliMRSAVRECorynebacterium jeikeiumClostridium difficile Candida spp.Legionella spp.Suspect in the patient that has been recently exposed to Imipenem/MeropenemImipenem-resistant organism
31、s in the hospitalized patient with sepsis Some Pseudomonas aeruginosa Some Acinetobacter spp.Xanthomonas maltophilia Burkholderia cepacia KPC Klebsiella spp.KPC E.coli MRSA VRE Corynebacterium jeikeium Clostridium difficile Candida spp.Legionella spp.AmikacinAmikacin,Doxycycline,Unasyn,PBBactrimBact
32、rim?Polymyxin B?Polymyxin BVancomycinLinezolidVancomcyinMetronidazoleFluconazoleQuinolones/MacrolidesAntimicrobials in green-Suggest NOT to use empiricallyA few location,PK/PD commentsUrinary tract infections:most antimicrobials reach good concentrations in the urine.Gram negative CNS infections:Cef
33、tazidime or Cefepime rather that Zosyn.?Meropenem rather than Imipenem?.Ideally use bactericidal agents.Aminoglycosides:Poor penetration to many sites(eye,CNS,lung).Poor volume of distribution in critically ill patients.Poor activity if environment has low pH and anaerobiosis(abscesses,intrabdominal
34、 infections,infected decubitus ulcers or severe diabetic foot infections).Vancomycin and MRSA:AUC/MIC ratio associated with outcomes(cut-off 400?).Some isolates may have MIC of 2,and may not respond to Vancomycin.Target trough differs according to site of infection.Beta-lactams have time-dependent k
35、illing.Aminoglycosides,quinolones and rifampin have concentration-dependent killing.Appropriate de-escalationDe-escalate by day 2-3 of therapy,when culture results become available.De-escalate to narrow spectrum agents if possible:MSSA and MSSE:use Nafcillin,Oxacillin or Cefazoline.E.coli,Klebsiella
36、 or Proteus susceptible to 1 gen cefalosporins:use Cefazoline.Enterococcus spp.susceptible to Penicillin:use PCN,Amoxicillin or Ampicillin.Pseudomonas aeruginosa susceptible to Piperacillin:use Piperacillin.Be careful with results of antimicrobial susceptibility for Enterobacter,Serratia,Citrobacter
37、,particularly in patients with severe infections(these organisms can de-repressed AmpC beta-lactamases)Remember that anaerobes are difficult to grow in the lab Need clinical judgment to decide if anaerobic coverage is needed(diabetic foot,infected decubs,intrabdominal or pelvic infections).Know how to interpret culture results.Resistance-Induced Antimicrobial Substitution and Public HealthCDC guidelines for STDsQuinolone Resistance in GCMainly for outpatient infectious diseases -Take into account the Public Health implications of not treating with active agentexamples:GCMDR TBHIV
