Empirical Therapy for Ventilation Associated Pneumonia Azar. Hadadi Associate Professor of Infectious Diseases

Empirical Antibiotic Therapy Empirical antibiotic therapy entails the initial selection of an antibiotic regimen that aims to be effective against any pathogen suspected of causing the infection. Empirical therapy has been classified as appropriate/adequate or inappropriate/inadequate based on the in vitro susceptibilities of the identified pathogens.

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

Antibiotic Selection In critically ill patients, the susceptibility of the bacteria isolated in a VAP depends on the duration of stay in the ICU and on mechanical ventilation as well as the previous use 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 VAP being caused by multidrug resistant pathogens, but occurring on days 2–4

Thus, antibiotic choice based on the time of pneumonia onset can lead to both over- and under treatment with broad-spectrum agents.

Early onset VAP Streptococcus pneumoniae Haemophilus influenzae Methicillin-sensitive Staphylococcus aureus Antibiotic-sensitive enteric Gram-negative bacilli Escherichia coli Klebsiella pneumoniae Enterobacter species Proteus species,

Late­Onset Ventilator­Associated Pneumonia 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 in the 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 NO

American Thoracic Society (ATS)/Infectious Diseases Society and America (IDSA) guidelines recommend local microbiological data and their own antibiograms Specific empiric treatment protocols

Empiric AB therapy for VAP in patients with NO risk factors for multidrug-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 OR

Empiric AB therapy for VAP in patients with late-onset disease B-Lactam/B-lactamase inhib.Piperacillin/tazobacta m4 ×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 Antipseudomonal fluoroquinolone Ciprofloxacin 3 ×400 mg Levofloxacin 1 ×750 mg Vancomycin 2 ×15mg/ kg Linezolid 2 ×600 mg OR PLUS OR 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 empiric coverage Synergy Prevent or delay the emergence of resistance

when the B -lactam agent is sufficiently broad (e.g., carbapenem) and there is no local epidemiologic evidence supporting the likelihood of highly resistant organisms, the benefit of combination therapy, even empirically, is unclear.

Antibiotics for MDR-GNB Carbapenems have constituted the mainstay of VAP for many years. Imipenem, meropenem and doripenem have similar spectrum although doripenem is the most active carbapenem against P aeruginosa

If the patient has a good clinical response to therapy, then it may be possible to reduce the number of antimicrobial agents, based on culture results. Even though initial empiric therapy can involve as many as 3 different antibiotics, in the absence of multidrug­resistant pathogens, therapy can be completed with a single agent.

De-escalation refers to use of microbiologic and clinical data to change from an initial broad- spectrum, multi-drug empiric therapy regimen to a therapy with fewer antibiotics and agents of narrower spectrum. This is a promising approach for optimizing the use of antibiotics 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 against multi-drug resistant GNB including A baumannii, P aeruginosa, extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae or Klebsiella-producing carbapanamase strains. Proteus spp, Providencia spp, Morganella morganii and Serratia marcescens are resistant

A multicenter randomized clinical trial (RCT) that is currently ongoing has been designed to assess the efficacy and safety of colistin compared to meropenem in the empirical therapy of VAP with high suspicion of MDR- GNB. The empirical use of colistin may justify in institutions where there is a high rate of infections due to MDR-GNB

Tigecycline Gram-positive organisms such as MRSA ESBL Enterobacteriaceae Acinetobacter and other multi-drug resistant (MDR) pathogens. including some colistin resistant strains Gram-negative pathogens with the exceptions of P aeruginosa and Proteus ssp.

MRSA VAP Vancomycin Linezolid

linezolid Better tissue penetration than vancomycin, but is bacteriostatic rather than bactericidal. Significantly greater chance of bacterial eradication, clinical cure, and hospital survival Linezolid should NOT be used empirically, however, but reserved for documented MRSA pneumonia. High Cost Thrombocytopenia

Linezolid Linezolid has high oral bioavailability (approximately 100%) Peripheral and optic neuropathy lactic acidosis Drug interactions with antidepressants, monoamine oxidase inhibitors, some analgesics and anticonvulsants

Teicoplanin The administration of high teicoplanin doses (12 mg/kg teicoplanin every 12 h the first 2 days followed by 12 mg/kg once daily) is needed to reach sufficient antibiotic concentrations in lung tissues at steady state. Do not recommend teicoplanin for VAP due to the uncertainties about the correct doses impossibility of level measurements

Daptomycin Bactericidal It is indicated for the treatment of SSTIs (6 mg/kg) and Staphylococcus aureus bloodstream infections right-sided infective endocarditis Daptomycin should not be used for patients with pneumonia due to the inhibition of daptomycin by Surfactant The main toxicities of daptomycin include eosinophilic pneumonia and skeletal muscle injury

PCT, the precursor of the thyroid hormone calcitonin, is also increased in the systemic inflammatory response to infection. What is procalcitonin? PCT was described as a marker of sepsis in 1993

In normal physiological conditions, PCT levels in the serum are low (0.1 ng/mL). In bacterial infection PCT is synthesized in various extrathyroidal neuroendocrine tissues. Systemic PCT secretion is a component of the inflammatory response that appears to be relatively specific to systemic bacterial infections. PCT

PCT becomes detectable within 2 to 4 hours after a triggering event and peaks by 12 to 24 hours. In the absence of an ongoing stimulus, PCT is eliminated with a half-life of 24 to 35 hours, making it suitable for serial monitoring.

Use of PCT as a VAP marker on the ICU

PCT PCT was shown to be elevated on an average 2 days prior to the clinical diagnosis of VAP and therefore can be used as an early marker for diagnosis of VAP

ICU &VAP 0.25< discontinue Abx; decrease of 80%, discontinuing Abx; >0.50 or < decreased 80%, continue Abx Decisions on antibiotic use should not be based solely on procalcitonin levels. If antibiotics are administered, repeat procalcitonin testing should be obtained every 2-3 days to consider early antibiotic cessation.

Conclusion Early­onset VAP in a patient with mild disease severity and no previous hospitalization, risk factors, or exposure to antibiotics can be managed with a third­generation cephalosporin, such as ceftriaxone, or an extended­spectrum quinolone, such as levofloxacin.

Conclusion If VAP is late in onset ( 5 days after hospitalization) or if other risk factors for a multidrug-resistant pathogen are present, then broad-spectrum combination therapy should be given initially.

Conclusion Late­onset hospital­acquired pneumonia, ventilator­associated pneumonia, and healthcare–associated pneumonia require combination therapy using an antipseudomonal cephalosporin, beta lactam, or carbapenem plus an antipseudomonal fluoroquinolone or aminoglycoside plus an agent such as linezolid or vancomycin to cover MRSA.

De­escalation therapy involves not only a reduction in the number of drugs used whenever possible, based on culture data, but also the shortening or stopping of therapy..