Slide 1

Empirical Therapy forVentilation AssociatedPneumonia

Azar. Hadadi

Associate Professor of Infectious Diseases

Empirical Antibiotic Therapy

•Empirical antibiotic therapy entails the initialselection of an antibiotic regimen that aims tobe effective against any pathogen suspectedof causing the infection.

• Empirical therapy has been classified asappropriate/adequate orinappropriate/inadequate based on the invitro susceptibilities of the identifiedpathogens.

Appropriate therapy means the pathogen issusceptible to the chosen antimicrobial drug.\An adequate antimicrobial regimen means thatappropriate antimicrobial drugs are selected,given in optimal dosages, by the correct route,in effective combinations, and for theappropriate duration.

Antibiotic Selection

•In critically ill patients, thesusceptibility of the bacteria isolatedin a VAP depends on the duration ofstay in the ICU and on mechanicalventilation as well as the previoususe of antibiotics.

VAP classification

•Early onset VAP (occurring on days 2–4)

•Late onset VAP (occurring on days ≥5).

• A third category is based on the risk of VAPbeing caused by multidrug resistantpathogens, but occurring on days 2–4

•Thus, antibiotic choice based on the time ofpneumonia onset can lead to both over- andunder treatment with broad-spectrum agents.

Early onset VAP

•Streptococcus pneumoniae

•Haemophilus influenzae

•Methicillin-sensitive Staphylococcus aureus

•Antibiotic-sensitive enteric Gram-negativebacilli Escherichia coli Klebsiella pneumoniaeEnterobacter species Proteus species ,

LateOnset VentilatorAssociatedPneumonia

•Gramnegative bacilli

–Pseudomonas aeruginosa

–Acinetobacter species

– Klebsiella species

– Enterobacter species

–Serratia species

Risk factors for MDR pathogens

•Antimicrobial therapy in preceding 90 d

•Current hospitalization of 5 d or more

•High frequency of antibiotic resistance in the community or inthe specific hospital unit

•Presence of risk factors for HCAP:

–Hospitalization for 2 d or more in the preceding 90 d

–Residence in a nursing home or extended care facility

–Home infusion therapy (including antibiotics)

–Chronic dialysis within 30 d

–Home wound care

–Family member with multidrug-resistant pathogen

•Immunosuppressive disease and/or therapy

Treatment of VAP

Empiric Antibiotic Therapy for VAP

Late Onset (>5 days) or Risk Factors for

Multi-drug Resistant (MDR) Pathogens

YES

Broad Spectrum

Antibiotic Therapy

For MDR Pathogens

Limited Spectrum

Antibiotic Therapy

American Thoracic Society (ATS)/Infectious DiseasesSociety and America (IDSA) guidelines recommend

•local microbiological data and their ownantibiograms

•Specific empiric treatment protocols

Empiric AB therapy for VAP in patients with NO risk factors formultidrug-resistant pathogens, Early onset

Ampicillin-Sulbactam

4 ×3g

Ceftriaxone 1 ×2g

Levofloxacin 1 ×750 mg

Moxifloxacin 1 ×400 mg

Ciprofloxacin 3 ×400 mg

Ertapenem 1 ×1g

Empiric AB therapy for VAP in patients with late-onset disease

B-Lactam/B-lactamaseinhib.Piperacillin/tazobactam4 ×4.5 g

Antipseudomonal ceph.Cefepime 2-3 ×1-2g

Ceftazidime 3 ×2g

Antipseudomonal carb.

Imipenem 4×500mg or 3×1g

Meropenem 3 ×1g

Aminoglycoside

Gentamicin 7 mg/kg per day

Tobramycin 7 mg/kg per day

Amikacin 20 mg/kg per day

Antipseudomonalfluoroquinolone

Ciprofloxacin 3 ×400 mg

Levofloxacin 1 ×750 mg

Vancomycin

2 ×15mg/ kg

Linezolid

2 ×600 mg

PLUS

Addition of coverage for MRSA if suspected

PLUS/ MINUS

Addition of MRSA Treatment

•Risk factors for MRSA

–History of MRSA infection or colonization

– Injection drug use

– History in the past year of hospitalization

– Residence in long-term care facility

– Dialysis

–Surgery

–Necrotizing or cavitary infiltrates, Empyema

–High Prevalence

Combination therapy

Broaden

the empiriccoverage

Synergy

Prevent or delaythe emergenceof resistance

•when the B -lactam agent is sufficiently broad(e.g., carbapenem) and there is no localepidemiologic evidence supporting thelikelihood of highly resistant organisms, thebenefit of combination therapy, evenempirically, is unclear.

Antibiotics for MDR-GNB

•Carbapenems have constituted the mainstayof VAP for many years.

• Imipenem, meropenem and doripenem havesimilar spectrum although doripenem is themost active carbapenem against P aeruginosa

•If the patient has a good clinical response totherapy, then it may be possible to reduce thenumber of antimicrobial agents, based on cultureresults.

•Even though initial empiric therapy can involve asmany as 3 different antibiotics, in the absence ofmultidrugresistant pathogens, therapy can becompleted with a single agent.

•De-escalation refers to use of microbiologicand clinical data to change from an initialbroad- spectrum, multi-drug empiric therapyregimen to a therapy with fewer antibioticsand agents of narrower spectrum. This is apromising approach for optimizing the use ofantibiotics while

Re-evaluate in 72 hours, Antibioic de-escalation

•Culture result

•Clinical status

•biomarker profile

•Narrow antbiotic regimen

•Consider stopping therapy

•-Check for improper dosage of antibiotics- Rule out complications- Cover for resistant pathogens-Use of adjunctive medications

Colistin

•The greatest level of in vitro activity againstmulti-drug resistant GNB including Abaumannii, P aeruginosa, extended spectrumbeta-lactamase (ESBL)-producingEnterobacteriaceae or

•Klebsiella-producing carbapanamase strains.

•Proteus spp, Providencia spp, Morganella

•morganii and Serratia marcescens areresistant

•A multicenter randomized clinical trial (RCT)that is currently ongoing has been designed toassess the efficacy and safety of colistincompared to meropenem in the empiricaltherapy of VAP with high suspicion of MDR-GNB .

•The empirical use of colistin may justify ininstitutions where there is a high rate ofinfections due to MDR-GNB

Tigecycline

•Gram-positive organisms such as MRSA

•ESBL Enterobacteriaceae

•Acinetobacter and other multi-drug resistant(MDR) pathogens. including some colistinresistant strains

•Gram-negative pathogens with the exceptionsof P aeruginosa and Proteus ssp.

MRSA VAP

•Vancomycin

• Linezolid

linezolid

•Better tissue penetration than vancomycin, but isbacteriostatic rather than bactericidal.

•Significantly greater chance of bacterialeradication, clinical cure, and hospital survival

•Linezolid should NOT be used empirically,however, but reserved for documented MRSApneumonia.

•High Cost

•Thrombocytopenia

Linezolid

•Linezolid has high oral bioavailability(approximately 100%)

•Peripheral and optic neuropathy

•lactic acidosis

•Drug interactions with antidepressants,monoamine oxidase inhibitors, someanalgesics and anticonvulsants

Teicoplanin

The administration of high teicoplanin doses (12mg/kg teicoplanin every 12 h the first 2 daysfollowed by 12 mg/kg once daily) is needed toreach sufficient antibiotic concentrations in lungtissues at steady state.

•Do not recommend teicoplanin for VAP due tothe uncertainties about the correct dosesimpossibility of level measurements

Daptomycin

•Bactericidal

•It is indicated for the treatment of SSTIs (6 mg/kg)and Staphylococcus aureus bloodstreaminfections right-sided infective endocarditis

•Daptomycin should not be used for patients withpneumonia due to the inhibition of daptomycinby Surfactant

•The main toxicities of daptomycin includeeosinophilic pneumonia and skeletal muscleinjury

PCT, the precursor of the thyroid hormonecalcitonin, is also increased in the systemicinflammatory response to infection.

What is procalcitonin?

PCT was described as a marker of sepsis in 1993

•In normal physiological conditions, PCT levels inthe serum are low (0.1 ng/mL).

•In bacterial infection PCT is synthesized in variousextrathyroidal neuroendocrine tissues.

•Systemic PCT secretion is a component of theinflammatory response that appears to berelatively specific to systemic bacterial infections.

PCT

•PCT becomes detectable within 2 to 4 hours aftera triggering event and peaks by 12 to 24 hours.

•In the absence of an ongoing stimulus, PCT iseliminated with a half-life of 24 to 35 hours,making it suitable for serial monitoring.

Use of PCT as a VAP marker onthe ICU

PCT

•PCT was shown to be elevated on an average 2days prior to the clinical diagnosis of VAP andtherefore can be used as an early marker fordiagnosis of VAP

ICU &VAP

•0.25< discontinue Abx;

•<0.50 or >decrease of 80%, discontinuing Abx;

•>0.50 or < decreased 80%, continue Abx

•Decisions on antibiotic use should not bebased solely on procalcitonin levels. Ifantibiotics are administered, repeatprocalcitonin testing should be obtained every2-3 days to consider early antibiotic cessation.

Conclusion

•Earlyonset VAP in a patient with mild diseaseseverity and no previous hospitalization, riskfactors, or exposure to antibiotics can bemanaged with a thirdgenerationcephalosporin, such as ceftriaxone, or anextendedspectrum quinolone, such aslevofloxacin.

Conclusion

•If VAP is late in onset ( 5 days afterhospitalization) or if other risk factors for amultidrug-resistant pathogen are present,then broad-spectrum combination therapyshould be given initially.

Conclusion

•Lateonset hospitalacquired pneumonia,ventilatorassociated pneumonia, andhealthcare–associated pneumonia requirecombination therapy using anantipseudomonal cephalosporin, beta lactam,or carbapenem plus an

•antipseudomonal fluoroquinolone oraminoglycoside plus an agent such as linezolidor vancomycin to cover MRSA.

•Deescalation therapy involves not only areduction in the number of drugs usedwhenever possible, based on culture data, butalso the shortening or stopping of therapy.