Drugs for Resp Inf Waller lecture Flashcards
Sites of Antibacterial Action
Cell wall synthesis Cell membrane synthesis Protein synthesis Nucleic acid metabolism Function of topoisomerases Folate synthesis
β-Lactam MOA, ADRs
Time-dependent; structural analogs of D-Ala-D-Ala
covalently bind penicillin-binding proteins (PBPs), inhibit transpeptidation
Penicillins Allergic reactions (0.7-10%) Anaphylaxis (0.004-0.04%) Nausea, vomiting, mild to severe diarrhea Pseudomembranous colitis
Cephalosporins
1% risk of cross-reactivity to penicillins
Diarrhea
Carbapenems
Nausea/vomiting (1-20%)
Seizures (1.5%)
Hypersensitivity
Vancomycin Mechanism of Action, ADRs
Inhibits cell wall synthesis binding with high affinity to D-Ala-D-Ala terminal of cell wall precursor units
ADRs: Macular skin rash, chills, fever, rash
Red-man syndrome (histamine release): extreme flushing, tachycardia, hypotension
Ototoxicity, nephrotoxicity (33% with initial trough > 20 mcg/mL)
FluoroquinoloneMechanism of Action, ADRs
Concentration-dependent, targets bacterial DNA gyrase & topoisomerase IV. Prevents relaxation of positive supercoils
GI 3-17% (mild nausea, vomiting, abdominal discomfort)
CNS 0.9-11% (mild headache, dizziness, delirium, rare hallucinations)
Rash, photosensitivity, Achilles tendon rupture (CI in children)
Protein Synthesis Inhibitors Mechanisms of Action
Aminoglycosides (30S)
Interferes with initiation
Causes misreading & aberrant proteins
Tetracyclines (30S)
Blocks aminoacyl tRNA acceptor site
Macrolides (50S)
Inhibits translocation
Clindamycin (50S)
Inhibits translocation
Linezolid (50S)
Blocks formation of initiation complex
Protein Synthesis InhibitorsADRs
Aminoglycosides (30S)
Ototoxicity, nephrotoxicity, neuromuscular block and apnea
Tetracyclines (30S)
GI, superinfections of C. difficile, photosensitivity, teeth discoloration
Macrolides (50S)
GI, hepatotoxicity, arrhythmia
Clindamycin (50S)
GI diarrhea, pseudomembranous colitis, skin rashes
Linezolid (50S)
Myelosuppression, headache, rash
Community-Acquired Pneumonia (CAP) stats, goal of treatment
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
CAP – Guidelines 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 less than 350 cells/mm3
Children under/ equal to 18 years
CAP – Initial Assessment
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
Severity of Illness Scores:
In conjunction: laboratory data, clinical evaluation, & physician interpretation
CURB-65 Confusion Uremia (BUN > 20 mg/dL) Respiratory rate (≥ 30 breaths/min) Low blood pressure SBP under 90 mmHg, DBP under 60 mmHg Age (≥ 65 Years)
Score 0-1: treat as an outpatient
Score 2: admit to hospital
Score ≥ 3: often require ICU care
CAP – General Medical vs. ICU
10% of hospitalized CAP patients require ICU stay
Use CURB-65 + minor criteria to determine need for ICU admission:
Multilobar infiltrates
WBC less than 4000 cells/mm3
PLT less than 100,000 cells/mm3
Core temperature less than 36 ˚C
Hypotension requiring aggressive fluid resuscitation
Two absolute indications for ICU admission: Mechanical ventilation Septic shock (+ vasopressors)
CAP – Diagnosis
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
CAP – Common Infecting Organisms
outpatient: strep pneumo, myco pneumo, H. flu, chlamydophila pneumoniae, respiratory viruses
hospitalized: Same plus legionella, aspiration
ICU- S penumo, staph aureus, legionalla, gram-negative bacilli, H flu
CAP – Infecting Organisms/Disease State
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
CAP – Other Infecting Organisms
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
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
Drug-resistant S. pneumoniae (DRSP)- who gets it?
Age under 2 years or > 65 years B-lactam use within previous 3 months Alcoholism Immunosuppressive illness or therapy Exposure to child at day care
CAP – Empiric Antimicrobial Guidelines: 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
CAP – Empiric Antimicrobial Guidelines: 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)
CAP – Empiric Antimicrobial Guidelines: 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)
CAP – Modifying Empiric Regimen- pseudomonas aeruginosa
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
CAP – Modifying Empiric Regimen- MRSA
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 leukocidin (PVL) necrotizing pneumonia: add clindamycin or use linezolid
CAP – Intravenous –> Oral Therapy
Transition to oral therapy: Hemodynamically stable Improving clinically: Temperature under/ equal 37.8 ˚C HR under/equal 100 bpm RR 24 breaths/min or less SBP ≥ 90 mmHg Arterial 02 saturation ≥ 90% Ability to maintain oral intake Normal mental status Tolerating oral medications Normal functioning GI tract
CAP – Duration of Therapy
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
HCAP, HAP & VAP
HCAP: history of hospitalization or exposure to healthcare settings
HAP: occurs 48 hours or more after admission
Leading cause of death among patients with hospital-acquired infections
Serious complications (pleural effusions, septic shock, renal failure) in 50%
VAP: arises 48-72 hours after endotracheal intubation
Estimated all-cause mortality 20-50% (13%)
Prolongs length of mechanical ventilation 7.6-11.5 days
Prolongs hospitalization 11.5-13.1 days
Excess cost $40,000 per patient
HAP and VAP microbiology
Microbiology: wide variety of pathogens and can be polymicrobial
Common pathogens Aerobic gram-negative E. coli K. pneumonia Enterobacter spp. P. aeruginosa Acinetobacter spp.
GPCs
S. aureus including MRSA (more common in diabetes, head trauma, those hospitalized in ICUs)
Oropharyngeal commensals Viridans group streptococci Coagulase-negative staphylococci Neisseria spp. Corynebacterium spp.
