Drugs for Respiratory Infections Flashcards

Question

Community-Acquired Pneumonia (CAP)

Answer 1

**•CAP + Influenza (2005)** ▫8th leading cause of death in the U.S. ▫\> 60,000 deaths due to pneumonia in U.S. **•Most severe manifestations in:** ▫Very young, elderly, chronically ill **•Goal of CAP treatment: eradicate organism, resolve clinical disease** ▫Antibiotics = mainstay of therapy ▫Therapy guided by organism and susceptibility ▫Must have knowledge of most likely infecting pathogen and local susceptibility

Answer 2

**•Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS)** ▫Management of Community-Acquired Pneumonia **•Excluded patients:** ▫Immunocompromised patients ▫Solid organ, bone marrow, or stem cell transplant ▫Those receiving chemotherapy ▫Long-term high dose corticosteroids (\> 30 days) ▫Congenital or acquired immunodeficiency ▫HIV with CD4 count \< 350 cells/mm3 ▫Children ≤ 18 years ▫ ▫

Answer 3

**•Assessment of severity:** ▫Outpatient, inpatient (non-ICU), ICU **•Avoid unnecessary admissions:** ▫25x greater cost inpatient vs. outpatient ▫Resume normal activities faster as outpatient ▫Hospitalization carries risks: thromboembolic events & superinfections

Answer 4

**•In conjunction: laboratory data, clinical evaluation, & physician interpretation** **•CURB-65** ▫Confusion ▫Uremia (BUN \> 19 mg/dL) ▫Respiratory rate (≥ 30 breaths/min) ▫Low blood pressure SBP \< 90 mmHg, DBP ≤ 60 mmHg ▫Age (≥ 65 Years) **•Pneumonia severity index (PSI)**

Answer 5

Score 0-1: treat as an outpatient Score 2: admit to hospital Score ≥ 3: admit to ICU

Answer 6

**•10% of hospitalized CAP patients require ICU stay** **•Use CURB-65 + minor criteria to determine need for ICU admission:** ▫Multilobar infiltrates ▫WBC \< 4000 cells/mm3 ▫PLT \< 100,000 cells/mm3 ▫Core temperature \< 36 ˚C ▫Hypotension requiring aggressive fluid resuscitation **•Two absolute indications for ICU admission:** ▫Mechanical ventilation ▫Septic shock (+ vasopressors)

Answer 7

**•Clinical findings:** ▫Cough, fever, sputum production, pleuritic chest pain **•Demonstrable infiltrate on CXR required:** ▫If negative but CAP suspected, initiate antibiotics and repeat CXR in 24-48 hours **•Culture** ▫Increased mortality & risk of treatment failure – if inappropriate antimicrobials used **•Additional diagnostic testing**

Answer 8

•Most valuable, time tested method for immediate ID of bacteria = gram stain

Answer 9

•Most valuable, time tested method for immediate ID of bacteria = gram stain

Answer 10

**•Underlying bronchopulmonary disease:** ▫H. influenzae ▫Moraxella catarrhalis ▫+ S. aureus during an influenza outbreak **•Chronic oral steroids or severe underlying bronchopulmonary disease, alcoholism, frequent antibiotic use:** ▫Enterobacteriaceae ▫Pseudomonas aeruginosa **•Classic aspiration pleuropulmonary syndrome in alcohol/drug overdose or in seizures with gingival disease or esophageal motility disorders:** ▫Anaerobes

Answer 11

**•Common viruses:** ▫Influenza ▫Respiratory syncytial virus (RSV) ▫Adenovirus ▫Parainfluenza virus **•Other viruses:** ▫Human metapneumovirus ▫Herpes simplex virus (HSV) ▫Varicella-zoster virus (VSV) ▫SARS-associated coronavirus

Answer 12

**•2-3% incidence:** ▫M. tuberculosis ▫Chlamydophila psittaci (psittacosis) ▫Coxiella burnetii (Q fever) ▫Francisella tularensis (tularemia) ▫Bordetella pertussis (whooping cough) ▫Endemic fungi Histoplasma capsulatum Coccidioides immitis Cryptococcus neoformans Blastomyces hominis

Answer 13

•Drug-resistant S. pneumoniae (DRSP) ▫Age \< 2 years or \> 65 years ▫B-lactam use within previous 3 months ▫Alcoholism ▫Immunosuppressive illness or therapy ▫Exposure to child at day care

Answer 14

**•Outpatient Recommendations** ▫Previously healthy Macrolide PO (azithromycin, clarithromycin) -OR- Doxycycline PO ▫DRSP risk (comorbidities, age \> 65 years, use of antimicrobials within 3 months) Respiratory fluoroquinolone PO (levofloxacin, moxifloxacin) -OR- B-lactam PO [high dose amoxicillin or amoxicillin- clavulanate preferred (alternates: ceftriaxone, cefuroxime)] PLUS a macrolide PO

Answer 15

**•Inpatient, Non-Intensive Care Unit Recommendations** Respiratory FQ IV or PO (levofloxacin, moxifloxacin) -OR- B-lactam IV (ceftriaxone, cefotaxime, or ampicillin preferred) PLUS macrolide IV (azithromycin)

Answer 16

**•Inpatient, Intensive-Care Unit Recommendations** B-lactam IV (ceftriaxone, cefotaxime, or ampicillin/sulbactam preferred) PLUS azithromycin IV -OR- B-lactam IV (ceftriaxone, cefotaxime, or ampicillin/sulbactam preferred) PLUS a respiratory FQ (levofloxacin, moxifloxacin

Answer 17

**•Pseudomonas aeruginosa risks:** ▫Structural lung disease (bronchiectasis) ▫Repeated COPD exacerbations Frequent corticosteroid and/or antibiotic use ▫Prior antibiotic therapy **•Treatment:** Antipseudomonal B-lactam IV (piperacillin-tazobactam, cefepime, imipenem, meropenem) PLUS either ciprofloxacin or levofloxacin -OR- Antipseudomonal B-lactam PLUS aminoglycoside (gentamicin) AND azithromycin -OR- Antipseudomonal B-lactam PLUS aminoglycoside AND antipneumococcal FQ

Answer 18

**•Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) risks:** ▫End-stage renal disease (dialysis) ▫Injection drug abuse ▫Prior influenza ▫Prior antibiotic use (especially FQ) **•Treatment:** ▫Add vancomycin IV or linezolid ▫Panton-Valentine leucocidin necrotizing pneumonia: add clindamycin or use linezolid

Answer 19

**•Transition to oral therapy:** ▫Hemodynamically stable ▫Improving clinically: Temperature ≤ 37.8 ˚C HR ≤ 100 bpm RR ≤ 24 breaths/min SBP ≥ 90 mmHg Arterial 02 saturation ≥ 90% Ability to maintain oral intake Normal mental status ▫Tolerating oral medications ▫Normal functioning GI

Answer 20

**•Minimum of 5 days treatment** ▫Most patients receive 7-10 days **•Must be afebrile for 48-72 hours** **•No more than 1 CAP-associated sign of clinical instability** **•Exception:** ▫Pseudomonas – 8 day course led to more relapse compared to 15 day course

Answer 21

* HCAP: history of hospitalization or exposure to healthcare settings * HAP: occurs 48 hours or more after admission ▫2nd most common nosocomial infection in the U.S. ▫Increases hospital length of stay ~7-9 days ▫Incidence: 5-10 cases per 1000 admissions •VAP: arises 48-72 hours after endotracheal intubation ▫Occurs in 9-27% of all intubated patients ▫Incidence increases with longer ventilation duration

Answer 22

**•Early onset (\< 4 days) vs. late onset (5+ days)** **•Common pathogens** ▫Aerobic gram-negative P. aeruginosa E. coli K. pneumoniae Acinetobacter spp. ▫GPCs MRSA (more common in diabetes, head trauma, those hospitalized in ICUs) ▫Oropharyngeal commensals Viridans group streptococci Coagulase-negative staphylococci Neisseria spp. Corynebacterium spp.

Answer 23

**•Pseudomonas aeruginosa** ▫Resistance caused by multiple efflux pumps ▫Decreased expression of outer membrane porin channel ▫Increasing resistance to: Piperacillin Ceftazidime Cefepime Imipenem Meropenem Aminoglycosides Fluoroquinolones

Answer 24

•Klebsiella, Enterobacter, Serratia ▫Klebsiella intrinsically resistant to ampicillin and can acquire resistance to cephalosporins and aztreonam à ESBL production ▫Enterobacter high frequency resistance development to cephalosporins during treatment ▫These bacteria may carry plasmid mediated AmpC- type enzymes (ESBL) which are carbapenem susceptible but CONCERNED about resistance May become resistant by loss of an outer membrane porin

Answer 25

**•MRSA** ▫\> 50% of ICU infections caused by S. aureus are methicillin-resistant ▫PBPs with reduced affinity for B-lactams ▫Concern for linezolid resistance but still rare **•DRSP** ▫Altered PBP ▫ALL MDR strains in US currently susceptible to vancomycin and linezolid

Answer 26

**•Radiographic infiltrate that is new or progressive** **•Clinical findings suggestive of infection:** ▫Fever ▫Purulent sputum ▫Leukocytosis ▫Decline in oxygenation

Answer 27

**•Potential pathogens:** ▫S. pneumoniae ▫H. influenzae ▫MSSA ▫Sensitive gram-negative: E. coli, K. pneumoniae, Enterobacter spp., Proteus spp., Serratia marcescens **•Treatment:** ▫Ceftriaxone OR ▫FQ (levofloxacin, moxifloxacin, ciprofloxacin) OR ▫Ampicillin/sulbactam OR ▫Ertapenem

Answer 28

**•Potential pathogens (MDR):** ▫P. aeruginosa ▫K. pneumoniae (ESBL+) ▫Acinetobacter ▫MRSA **•Treatment:** ▫Antipseudomonal cephalosporin (cefepime, ceftazidime) OR antipseudomonal carbapenem (imipenem, meropenem) OR B-lactam/B-lactamase inhibitor (piperacillin-tazobactam) PLUS ▫Antipseudomonal FQ (ciprofloxacin, levofloxacin) OR aminoglycoside (gentamicin, tobramycin) PLUS ▫Linezolid OR vancomycin

Answer 29

**•Combination therapy recommended to ensure at least one agent is active against the often MDR pathogen** **•Often cited reasons for combination therapy:** ▫To prevent resistance Evidence not well documented ▫To add synergy for treatment of P. aeruginosa Only proven valuable in neutropenia or bacteremia **•Use monotherapy when possible**

Answer 30

**•VAP – good clinical response after 6 days** ▫Prolonged courses leads to MDR pathogen colonization **•Shorten duration to as short as 7 days (traditional 14-21 days)** ▫Unless P. aeruginosa (8 days led to relapse à requires longer treatment course)

Answer 31

**•Streptococcus pneumoniae** ▫Non-resistant Penicillin G Amoxicillin ▫Resistant Chosen on basis of susceptibility: Cefotaxime, ceftriaxone, levofloxacin, moxifloxacin, vancomycin, linezolid **•Haemophilus influenzae** ▫Non-B-lactamase producing Amoxicillin ▫B-lactamase producing 2nd or 3rd generation cephalosporin, amoxicillin/clavulanate

Answer 32

**•Mycoplasma pneumoniae** ▫Macrolide (azithromycin, clarithromycin), tetracycline (doxycycline) **•Chlamydophila pneumoniae** ▫Macrolide (azithromycin, clarithromycin), tetracycline (doxycycline) **•Chlamydophila psittaci** ▫Doxycycline **•Legionella spp.** ▫Fluoroquinolone, azithromycin, doxycycline

Answer 33

**•Enterobacteriaceae (Klebsiella, E. coli, Proteus)** ▫3rd or 4th generation cephalosporin, carbapenem (if ESBL producer) **•Pseudomonas aeruginosa** ▫Antipseudomonal B-lactam PLUS ciprofloxacin, levofloxacin, or an aminoglycoside **•Anaerobe (aspiration): Bacteroides, Fusobacterium, Peptostreptococcus** ▫B-lactam/B-lactamase inhibitor, clindamycin

Answer 34

**•Staphylococcus aureus** ▫Methicillin-sensitive Antistaphylococcal penicillin (nafcillin, oxacillin, dicloxacillin) ▫Methicillin-resistant Vancomycin or linezolid **•Influenza virus** ▫Oseltamivir, zanamivir

Answer 35

**•Pneumocystis jiroveci (P. carinii pneumonia)** ▫Trimethoprim/sulfamethoxazole **•Bordetella pertussis** ▫Azithromycin, clarithromycin **•Coccidioides spp.** ▫No treatment necessary if normal host Itraconazole, fluconazole • •Histoplasmosis and Blastomycosis ▫Itraconazole

Answer 36

**•Each year, 5-20% of population infected** **•In the U.S.:** ▫36,000 deaths ▫\> 200,000 hospitalizations **•Transmission:** ▫Respiratory droplets (cough, sneeze, talk) ▫Contaminated surfaces ▫Incubation: 1-4 days (average 2 days) ▫Viral shedding: day after symptoms to 5-10 days after illness onset

Answer 37

**•Symptoms (abrupt onset):** ▫Fever ▫Myalgia ▫Headache ▫Malaise ▫Non-productive cough ▫Sore throat ▫Rhinitis **•Symptoms resolve after 3-7 days (uncomplicated)** ▫Cough/malaise can last \> 2 weeks

Answer 38

**•Oseltamivir (PO), zanamivir (INH)** **•MOA: analogs of sialic acid, interferes with release of progeny influenza virus from infected host cell** •**PK**: ▫Oseltamivir – orally administered pro-drug, activated by hepatic esterases, t1/2 6-10 hours, glomerular filtration and tubular secretion (renally adjust) ▫Zanamivir – 10-20% reaches lungs, remainder deposits in oropharynx, t1/2 2.8 hours, 5-15% absorbed and excreted in urine with minimal metabolism

Answer 39

•**ADRs** ▫Oseltamivir – nausea, vomiting, abdominal pain (5- 10%), headache, fever, diarrhea, neuropsychiatric effects Approved for children ≥ 1 year ▫Zanamivir – cough, bronchospasm, decrease in pulmonary function (reversible), nasal/throat discomfort, not recommended in underlying airway disease Approved for children ≥ 7 years

Answer 40

•**Resistance**: ▫Point mutation in viral hemagglutinin (HA) or neuraminidase (NA) surface proteins -97.4% seasonal H1N1 resistant to oseltamivir 2008-2009 -Still susceptible to other drugs **•Therapeutic use:** ▫Influenza prophylaxis (household and institutional) ▫Influenza treatment

Answer 41

**•Amantadine (PO), rimantadine (PO)** **•MOA: block M2 proton ion channels of virus inhibiting uncoating of viral RNA within host cell** ▫Active against influenza A only **•PK:** ▫Amantadine – t1/2 12-18 hours, excreted unchanged in the urine, (renally adjust) ▫Rimantadine – 4-10x more active in vitro, t1/2 24-36 hours, extensive hepatic metabolism (renal and hepatic adjustment)

Answer 42

•ADRs: ▫GI (nausea, anorexia) ▫CNS (nervousness, insomnia, light-headedness) ▫Severe behavioral changes ▫Delirium ▫Agitation ▫Seizures •Resistance: point mutations, marked resistance limiting use of these agents

Answer 43

**•Acyclovir (PO, IV, topical), valacyclovir (PO)** **•MOA: three phosphorylation steps for activation, first step via virus specific thymidine kinase. Inhibits DNA synthesis:** ▫Competition with deoxyGTP for DNA polymerase à binds DNA template irreversible complex ▫Chain termination following incorporation into viral DNA

Answer 44

**•PK:** ▫Acyclovir – bioavailability 15-20%, t1/2 2.3-3 hours, 20 hours in anuria, diffuses into most tissues and body fluids (including CSF) ▫Valacyclovir – L-valyl ester of acyclovir, rapidly hydrolyzed in liver, serum levels 3-5x greater than PO acyclovir, bioavailability 54-70%, t1/2 2.5-3.3 hours **•Therapeutic use:** genital herpes (treatment, prophylaxis, suppression), varicella, HSV encephalitis, neonatal HSV treatment **•ADRs:** nausea, diarrhea, headache

Answer 45

**•Ganciclovir (PO, IV), valganciclovir (PO)** **•MOA:** acyclic guanosine analog, requires activation by triphosphorylation before inhibiting DNA polymerase. Termination of DNA elongation. •**PK**: ▫Ganciclovir – t1/2 4 hours, intracellular t1/2 16-24 hours, clearance related to CrCl ▫Valganciclovir – L-valyl ester, bioavailability 60% **•Therapeutic use:** CMV retinitis treatment, CMV prophylaxis •**ADRs**: myelosuppression, nausea, diarrhea, fever, peripheral neuropathy

Answer 46

•Common fungi of clinical interest: ▫Candida albicans ▫Histoplasma capsulatum ▫Cryptococcus neoformans ▫Coccidioides immitis ▫Aspergillus spp. ▫Blastomyces dermatitidis

Answer 47

**•Ergosterol found in cell membrane of fungi (compared to cholesterol used in bacteria and human cells)** **•MOA:** inhibits fungal cytochrome P450, reducing production of ergosterol ▫Selective toxicity due to greater affinity for fungal rather than human cytochrome P450 enzymes

Answer 48

•**Therapeutic use:** wide spectrum of activity against Candida spp, blastomycosis, coccidiodomycosis, histoplasmosis, and even Aspergillus (itraconazole, voriconazole) **•ADRs:** minor GI upset, abnormalities in liver enzymes **•Drug interactions!!**

Answer 49

**•Fluconazole (Diflucan) PO, IV** ▫PK: water soluble, good CSF penetration, high PO bioavailability ~96% **•Itraconazole PO** ▫PK: drug absorption increased by food and low gastric pH **•Voriconazole (Vfend) PO, IV** ▫PK: well absorbed, bioavailability \> 90% ▫ADRs: visual changes, photosensitivity

Answer 50

* **MOA**: binds ergosterol, changes permeability of cell, forms pores in membrane * **PK**: ▫Insoluble in water, variety of lipid formulations available, poorly absorbed PO, t1/2 15 days, only 2- 3% of blood level reaches CSF **•Therapeutic use:** broadest spectrum of activity, useful in life-threatening infections but very toxic **•ADRs:** infusion related (fever, chills, vomiting, headache), cumulative toxicity (renal damage)

Answer 51

**•Caspofungin, micafungin, anidulafungin (IV)** **•MOA:** inhibits synthesis of B(1-3)-glucan, disrupts fungal cell wall, and causes cell death **•Therapeutic use:** Candida and Aspergillus **•ADRs:** minor GI, flushing

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Drugs for Respiratory Infections Flashcards

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