University:
West Coast University
Course:
PHAR 837 | IPC Infectious Diseases I
Academic year:

2024
Views:

119

Pages:

27
Author:

Asal A.

1 APPROPRIATE USE OF 57 37 Yo 09 25 ANTI-INFECTIVE AGENTS Su Lee, Pharm.D., M.S., BCIDP 4 Systemic Approach for Selection of Antimicrobials • Confirm the presence of infection • Careful history and physical • Signs/Symptoms • Identification of the pathogen • • • • Collection of infected material Gram Stains Serology EmÉÉÉtherapy Culture and sensitivity so gig • Selection of presumptive therapy considering site of infection • Host Factors • Drug Factors • Monitoring therapeutic response • Clinical assessment • Laboratory tests • Assessment of therapeutic failure 5 How do we know if the patient has an infectious disease? • Definition of Fever1 : oral temperature of • A single measurement ≥ 38.3°C (101.0°F) or • A temperature of ≥ 38.0°C (100.4°F) over 1 hour period. • Signs and symptoms • WBC (neutrophils) • Neutrophil: Segmented vs. Band • Left shift • indicate abundant neutrophils>=80% and/or • Bandemia, band>=10% • Procalcitonin levels2 • Precursor of calcitonin, secreted by C cells of thyroid gland and K cells of lung (Baseline chronic diseases have high PCT)- Caution in patients with immuno-suppression (including HIV), CF, pancreatitis, trauma, pregnancy, high volume transfusion, malaria Schuetz P et al. Clin Chem Lab Med 2019; 57(9):1308-1318 • When stimulated by endotoxin, PCT is rapidly produced by parenchymal tissue throughout the body, which related to diverse bacterial infections in pneumonia, Sepsis, CNS infections (not related in bone inf, always high in renal failure) • CRP, ESR (non-specific inflammatory marker) • Local signs • Symptoms • Radiology test 1Freifeld 2Tunkel AG et al, CID, 2011;52(15 Feb):e56-93 AR et al., CID, 2017;64(15 Mar): e34-e65 6 Identification of the Pathogen • Culture • Timing • Blood culture • Urine culture • Respiratory culture • Wound culture • Fluid culture • CSF culture cerebrospinal 850 • Sensitivity Test • Interpreting Results • Infection : with Signs and Symptoms (S/S) of Infection • Colonization : Micro-organisms are on the body without causing infections (NO S/S) • Contamination 7 BE Empiric Drug Selection • Regional Resistance Patterns • Local sensitivity patterns : Antibiogram • Basic epidemiology of infection • Pt’s living condition (community vs. institution) • Recent travel history • Exposure to infected person (Children) • Recent exposure to other health-care system • Hospitalization in 90 days • Recent Antimicrobial Therapy • Previous organisms identified from the patient and associated antimicrobial susceptibility testing data in the last 12 months 1Kalil AC et al, CID, 2016;63(1 Sept):e61 • Antibiotic exposure within the past 30 days Tamma PD et al, CID, 2023; • IV antibiotics within 90 days1 : resistant organism https://doi.org/10.1093/cid/ciad428 8 Empiric Drug Selection : Host Factors • Drug allergies • • • • • • -What to ask? When, reactions, what drug -Cross reactivities Age -Potential pathogens can change with age (ex. meningitis) -Pediatric or geriatric consideration Immune function Pregnancy Organ function (renal dose adjustment) Chronic disease status -Cystic fibrosis or COPD : pathogens peptidase inhibitdehydro -Seizure : avoid imipenem/cilastatin Concurrent Medications -Drug interactions Ma empti s 13 Penicillin Allergy and Cross Reactivity • Cross-reactivity between penicillin and cephalosporin occurs in about 2% of cases. • Patients with anaphylaxis after penicillin, almost 40% have demonstrated cross-reactivity with a cephalosporin, although almost exclusively with amino-cephalosporins. Appears driven by side chains. • • • • • Common Amino R1 Group Common Methoxyimino R1 Group Amipicillin, Amoxicillin Cefaclor, Cephalexin, Cefadroxil Ceftriaxone, Cefotaxime, Cefuroxime, Cefepime, Ceftazidime, Cefpodoxime cf. Cefazolin no shared side chain with penicillin Cross-reactivity between penicillins and carbapenems is less than 1% No cross reactivity between penicillins and monobactams (cf. Ceftazidime vx. Aztreonam) Do NOT challenge patient with documented IgE mediated reaction (anaphylaxis) or laryngospasm For non-IgE reactions, depending on similarity of side chain, may get skin rash but not anaphylaxis Many childhood reaction were likely reactions to IM penicillin with procaine; procaine reaction not the penicillin Shenoy ES et. al, JAMA 2019:321(2):188-199 14 Treatment in a Patient with Penicillin Allergy in IDSA guidelines • Patient with anaphylactic reaction, life-threatening reactions, severe reaction • - AVOID all B- lactams except Aztreonam I • - For G(-) infections, Aztreonam, antipseudomonal FQs flamingos • - For G(+) infections, Clindamycin, Vancomycin, or other MRSA agents • Patient with mild skin reactions • - AVOID penicillin • - Cephalosporins (2%) or Carbapenems (1%) chance of mild skin reactions • FOR NAPLEX QUESTIONS • AVOID ALL B-LACTAMS except Aztreonam FOR SAFETY Staicu ML, Evaluation of Antibiotic Allergies, in IDSAP 2021 Book 1 Infections in Immunocompromised Patients 16 Empiric Drug Selection : Drug Factors • Pharmacodynamics • Pharmacokinetics -Tissue penetration -Drug interactions -Renal dose adjustment • Drug Toxicities 17 important Drug-Drug Interactions Eet • Which classes of anti-infective have the most drug-drug interactions? • Fluoroquinolones(FQ): Chelation, Enz e • Tetracycline: Chelation ap3A4 seizeagitation • Carbapenems decrease valproate absorption : ↑SZ podorithromisin agitation • Macrolides (X) (azithromycin (C)) – Simvastatin/atorvastatin↑convention intonation clothing presents • INR ↑ with warfarin : Clarithromycin, FQs, Fluconazole, TMP/SMX, metronidazole loptbleed • Rifampin (Enzyme inducer) is the winner : INR ↓ with warfarin Ambalism • Azole antifungals(Fluconazole, Itraconazole, Voriconazole…) • Anti-retroviral agents mainstage • NNRTIs (Non-nucleoside reverse transcriptase) • Protease Inhibitors Drug Interactions - CYP 450-3A4 CYP 450-3A4 Decrease Metabolism (Inhibitors) androgens atorvastatin benzodiazepines buspirone cimetidine clarithromycin clotrimazole corticosteroids cyclosporine dexamethasone diazepam diltiazem erythromycin estrogens felodipine fluconazole itraconazole ketoconazole lovastatin methylprednisolone midazolam nefazodone nicardipine Increase Absorption fatty meals (Itraconazole tabs) CYP 450-3A4 Increase Metabolism omeprazole oral contraceptives Other CYP 450-3A4 inhibitors posaconazole protease inhibitors simvastatin sirolimus tacrolimus triazolam verapamil voriconazole carbamazepine isoniazid (INH) nafcillin Other CYP 450-3A4 inducers pentobarbital phenobarbital phenytoin rifabutin rifampin Decrease Absorption antacids food H-2 blockers proton pump inhibitors 18 19 Drug Interactions - CYP 450 2C9 Inhibitor 2C9 Substrate 2C19 Inhibitor 2C19 Substrate fluconazole ketoconazole voriconazole amitriptyline celecoxib diclofenac fluoxetine fluvastatin glipizide glyburide ibuprofen ibersartan losartan meloxicam naproxen phenytoin piroxicam rosiglitazone suprofen tamoxifen tolbutamide torsemide voriconazole warfarin cimetidine felbamate fluoxetine fluvoxamine indomethacin ketoconazole lansoprazole modanafil omeprazole paroxetine ticlopidine tomipramate voriconazole amitriptyline carisoprodol citalopram clomipramine cyclophosphamide diazepam imipramine indomethacin lanoprasole nelfinavir nilutamide omeprazole pantoprazole phenobarbital phenytoin primidone progesterone propranolol teniposide voriconazole warfarin 2C9 Inducer phenytoin phenobarbital rifampin secobarbital 2C19 Inducer carbamazepine norethindrone phenytoin prednisone rifampin 20 43817 Drug Factors : PK ADME • Absorption • Fosfomycin PO : only FDA approved for uncomplicated UTI d/t poor pencay ay absorption • Distribution : CNS penetration depends on inflammation • No CNS penetration: Cefazolin, pip/taz 2054N a• Ceftriaxone pogey • Metabolism • Elimination • Renal dose adjustment • Penicillins (except nafcillin, oxacillin) e • Cephalosporins (except ceftriaxone) • Carbapenems • Monobactam • Fluoroquinolone (except moxifloxacin) • Aminoglycosides Avelot • Vancomycin • Daptomycin • Colistin (not polymyxin B) • Hepatic dose adjustment • Metronidazole Roth 921 off V91 Abogff arent 21 Empiric Drug Selection : Drug Factors Drug Toxicities • Nephrotoxicity : -aminoglycosides, polymyxins, vancomycin, Zosyn (Piperacillin/Tazobactam) • Ototoxicity : -aminoglycosides, vancomycin, azithromycin • Seizure : -imipenem/cilastatin, cefepime (renally impaired case), B-lactams • Neurotoxic effects : -polymyxins, isoniazid, FQs, minocycline, etc • Hematologic abnormalities -Chlorampenicol, beta-lactams (especially nafcillin), trimethoprim, linezolid, and vancomycin • Photosensitivity : -FQ, sulfa, tetracyclines, macrolides rangeUsg Normal 22 soInterval Prolongation QTc • EKG, NOT Echocardiogram • FQ (Moxi > Levo > Cipro), macrolide, telavancin, fluconazole (most of azole antifungals except isavuconazole), hydroxychloroquine • > 500 msec, or > 60 msec prolongation from baseline increases risk of torsades and ventricular fibrillation Atypical • Low serum K and/or Mg increases risk of QTc prolongation then any • Concomitant drugs increase risk: e.g., antiarrhythmics, antipsychotics, mefloquine, fosphenytoin • None of currently marketed FQs are at high risk when used alone; problem is concomitant drugs, electrolyte abnormalities 23 Empiric Drug Selection : Drug Factors • Cost • Direct cost • Indirect cost • Newer drug vs. Older drugs1 • MRSA inf. : • Vancomycin IV ($50/day) • Linezolid IV ($150/day), PO Tablet ($ 6-360/day), vs. Solution ($70/day) • Ceftaroline IV ($460/day) • Daptomycin IV ($535/500 mg/day) • Delafloxacin IV ($ 300/day) vs. PO ($160/day) • IV vs PO • Once daily vs. QID 1Lexicomp, accessed on 8/25/19 24 Combination Therapy • Advantages 1 53 18 • Broadening the spectrum • Intra-abdominal infections : G(-) plus anaerobes • Pneumonia : typical plus atypicals • Synergism with aminoglycosides • G(+): Enterococcus, Staphylococcus • G(-): Pseudomonas, or Carbapenem Resistant Enterobacterales • Preventing Resistance • Disadvantages • Cost, toxicity, antagonism? (static and cidal) 25 Monitoring Therapeutic Response • Culture/Sensitivity • De-escalation = stream down therapy to narrower spectrum • Bug-drug mismatch • WBC ( be careful with steroid use) • Vital Signs including Tmax24 (Fever) • Procalcitonin Levels (Pneumonia, Sepsis, CNS infections, not for HD, bone inf.) • Organ functions (Renal, hepatic) • Signs/Symptoms (ex. chest x-ray, urinalysis) • TDM (Therapeutic Drug Monitoring) • Drug specific monitoring parameters • IV/PO switch (S/S improves, pt is tolerable to PO meds) • Duration of therapy 26 Failure of Antimicrobial Therapy • Re-evaluation in 48-72h • Drug factors : • penetration, sub-therapeutic dose, inappropriate spectrums coverage • Host factors • immune function, specific populations (3rd space, pregnant, pediatric/geriatric), comorbidity, concurrent medications, previous antibiotic use, previous medical history, inappropriate source control(e.g. abscess or foreign body) • Micro-organisms • Unidentified pathogens (fungal or viral) • Primary drug resistance • Enterococcus against cephalosporins, S. aureus against penicillins • Acquired drug resistance • ESBL, FQ resistance, carbapenem resistance, etc 27 Aggressive approach for empiric antimicrobial therapy Determine Suspect infection potential pathogens and resistance rates Isolate pathogen Initiate broad spectrum Abx (often multiple drugs) Patient deteriorates or pathogen identified Narrow antibiotic spectrum based on susceptibility results as resistant to therapy (De-escalation or Stream down) Successful Outcome Change antibiotics 28 Antimicrobial Stewardship Main Goals • To optimize antimicrobial Activities • Selection • Dosing • Duration • Route of administration • While minimizing • adverse drug events • emergency of antimicrobial resistance TEAM: Multidisciplinary Group • microbiology • infection control, Administration • information technology • pharmacy (ID-trained clinical pharmacists) • physicians (ID specialist) • Formulary restriction • Prospective audit and feedback of • • • • antimicrobial prescriptions to clinicians Education Use of clinical order sets and guidelines De-escalation of therapy Intravenous to oral antimicrobial conversion with the following criteria • • • • Susceptible to an appropriate oral agent Hemodynamically stable Reasonable source control Sufficient intestinal absorption 29 Summary • Factors to consider for selecting an appropriate antimicrobial regimen • • • Host (allergy, S/S, site of infection, pathogens & sensitivity, immune functions, organ functions, age, co-morbidity, concurrent drugs) Drug (Pharmacodynamics, bactericial vs. bacteristatic, pharmacokinetics ADME, DI, PO vs. IV, toxicity) Monitoring parameters of infectious diseases • S/S, vitals, WBC, culture and sensitivity (C/S), drug levels, radiology, etc 30 Appendix : Drug of Choices and Alternatives based on In-Vitro susceptibilities 31 32 33

Appropriate Use of Anti-infective Agents

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