Drugs for Resp Inf Waller lecture

Question 1

Sites of Antibacterial Action

Answer 1

Cell wall synthesis
Cell membrane synthesis
Protein synthesis
Nucleic acid metabolism
Function of topoisomerases
Folate synthesis

Question 2

β-Lactam MOA, ADRs

Answer 2

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

Question 3

Vancomycin Mechanism of Action, ADRs

Answer 3

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)

Question 4

FluoroquinoloneMechanism of Action, ADRs

Answer 4

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)

Question 5

Protein Synthesis Inhibitors Mechanisms of Action

Answer 5

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

Question 6

Protein Synthesis InhibitorsADRs

Answer 6

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

Question 7

Community-Acquired Pneumonia (CAP) stats, goal of treatment

Answer 7

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

Question 8

CAP – Guidelines excluded patients

Answer 8

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

Question 9

CAP – Initial Assessment

Answer 9

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

Question 10

CAP – General Medical vs. ICU

Answer 10

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)

Question 11

CAP – Diagnosis

Answer 11

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

Question 12

CAP – Common Infecting Organisms

Answer 12

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

Question 13

CAP – Infecting Organisms/Disease State

Answer 13

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

Question 14

CAP – Other Infecting Organisms

Answer 14

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

Question 15

Drug-resistant S. pneumoniae (DRSP)- who gets it?

Answer 15

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

Question 16

CAP – Empiric Antimicrobial Guidelines: Outpatient recommendations

Answer 16

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

Question 17

CAP – Empiric Antimicrobial Guidelines: Inpatient, Non-Intensive Care Unit Recommendations

Answer 17

Respiratory FQ IV or PO (levofloxacin, moxifloxacin)
-OR-
B-lactam IV (ceftriaxone, cefotaxime, or ampicillin preferred) PLUS macrolide IV (azithromycin)

Question 18

CAP – Empiric Antimicrobial Guidelines: Inpatient, Intensive Care Unit Recommendations

Answer 18

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)

Question 19

CAP – Modifying Empiric Regimen- pseudomonas aeruginosa

Answer 19

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

Question 20

CAP – Modifying Empiric Regimen- MRSA

Answer 20

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

Question 21

CAP – Intravenous –> Oral Therapy

Answer 21

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

Question 22

CAP – Duration of Therapy

Answer 22

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

Question 23

HCAP, HAP & VAP

Answer 23

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

Question 24

HAP and VAP microbiology

Answer 24

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.

Question 25

HAP & VAP – Diagnosis

Answer 25

Radiographic infiltrate that is new or progressive

Clinical findings suggestive of infection:
Fever
Purulent sputum
Leukocytosis
Decline in oxygenation

Question 26

HAP & VAP – Antibiogram

Answer 26

Profile of antimicrobial susceptibility, shows percentages of organisms tested that are susceptible to a range of antimicrobial drugs

2016 guidelines recommend data should be used to:
Decrease unnecessary dual gram-negative and empiric MRSA coverage

Goals:
Minimize patient harm
Decrease exposure to unnecessary antibiotics
Reduce development of resistance

Question 27

VAP – MDR Pathogens Risk factors:

Answer 27

IV antibiotic use within the previous 90 days
Septic shock at the time of VAP
ARDS preceding VAP
≥ 5 days of hospitalization prior to the occurrence of VAP
Acute renal replacement therapy prior to VAP onset
Treatment in an ICU in which > 10% of gram-negative isolates are resistant to an agent being considered for monotherapy
Treatment in an ICU in which local antimicrobial susceptibility rates are not known
Treatment in a unit in which > 10-20% of S. aureus isolates are methicillin-resistant
Treatment in a unit in which the prevalence of MRSA is not known

Question 28

HAP – Risk Factors

Answer 28

Increased mortality
Ventilatory support for HAP
Septic shock

MDR Pseudomonas, other gram-negative bacilli, and MRSA
IV antibiotics within the past 90 days

MDR Pseudomonas and other gram-negative bacilli
Structural lung disease
Respiratory specimen with numerous & prominent gram-negative bacilli

MRSA
Treatment in unit > 20% of S. aureus isolates are methicillin-resistant
Treatment in a unit in which the prevalence of MRSA is not known

Question 29

HAP – Empiric Therapy

Answer 29

For patients WITHOUT risk factors or increased risk of mortality
Piperacillin-tazobactam -OR- cefepime -OR- imipenem -OR- meropenem -OR- levofloxacin

For patients WITH risk factors OR increased risk of mortality
Antipseudomonal B-lactam -PLUS-
Antipseudomonal fluoroquinolone -OR- aminoglycoside -OR- polymyxin
-PLUS- MRSA coverage

If risk factors for MRSA absent, eliminate MRSA coverage

If risk factors for MRSA present but not MDR Pseudomonas, only one agent with Pseudomonas coverage required plus MRSA coverage

Question 30

HAP & VAP – Duration of Therapy

Answer 30

7-day course of antibiotics recommended

May adjust based on rate of improvement of clinical, radiologic, and laboratory parameters

Question 31

Strep Pneumo DOC

Answer 31

Non-resistant
Penicillin G
Amoxicillin

Resistant
Chosen on basis of susceptibility:
Cefotaxime, ceftriaxone, levofloxacin, moxifloxacin, vancomycin, linezolid

Question 32

H Flu DOC

Answer 32

Non-B-lactamase producing
Amoxicillin

B-lactamase producing
2nd or 3rd generation cephalosporin, amoxicillin/clavulanate

Question 33

Mycoplasma pneumoniae DOC

Answer 33

Macrolide (azithromycin, clarithromycin), tetracycline (doxycycline)

Question 34

Chlamydophila pneumoniae DOC

Answer 34

Macrolide (azithromycin, clarithromycin), tetracycline (doxycycline)

Question 35

Chlamydophila psittaci DOC

Answer 35

doxycycline

Question 36

Legionella spp. DOC

Answer 36

Fluoroquinolone, azithromycin, doxycycline

Question 37

Enterobacteriaceae (Klebsiella, E. coli, Proteus)

DOC

Answer 37

3rd or 4th generation cephalosporin, carbapenem (if ESBL producer)

Question 38

Pseudomonas aeruginosa DOC

Answer 38

Antipseudomonal B-lactam PLUS ciprofloxacin, levofloxacin, or an aminoglycoside

Question 39

Anaerobe (aspiration): Bacteroides, Fusobacterium, Peptostreptococcus
DOC

Answer 39

B-lactam/B-lactamase inhibitor, clindamycin

Question 40

Staphylococcus aureus DOC

Answer 40

Methicillin-sensitive
Anti-staphylococcal penicillin (nafcillin, oxacillin, dicloxacillin)

Methicillin-resistant
Vancomycin or linezolid

Question 41

Influenza virus

DOC

Answer 41

Oseltamivir, zanamivir

Question 42

Pneumocystis jiroveci (P. carinii pneumonia)
DOC

Answer 42

Trimethoprim/sulfamethoxazole

Question 43

Bordetella pertussis DOC

Answer 43

Azithromycin, clarithromycin

Question 44

Coccidioides spp. DOC

Answer 44

No treatment necessary if normal host

Itraconazole, fluconazole

Question 45

Histoplasmosis and Blastomycosis DOC

Answer 45

Itraconazole

Question 46

Influenza stats and transmission

Answer 46

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

Question 47

Influenza symptoms

Answer 47

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

Question 48

Neuraminidase Inhibitors

Answer 48

Oseltamivir (PO), zanamivir (INH), peramivir (IV)

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
Peramivir – IV administration as a single-dose, t1/2 20 hours, excreted in urine (90% unchanged)

Question 49

Neuraminidase Inhibitors ADRs

Answer 49

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

Peramivir – diarrhea, increased serum glucose, neutropenia, insomnia
Approved for adults ≥ 18 years

Question 50

Neuraminidase Inhibitors resistance and therapeutic use

Answer 50

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

Question 51

M2 Channel Blockers

Answer 51

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)

Question 52

M2 Channel Blockers ADRs, resistance

Answer 52

GI (nausea, anorexia)
CNS (nervousness, insomnia, light-headedness)
Severe behavioral changes
Delirium
Agitation
Seizures

Resistance: point mutations, marked resistance limiting use of these agents

Question 53

Acyclovir (PO, IV, topical), valacyclovir (PO)

Answer 53

for HSV and VSV

MOA: three phosphorylation steps for activation, first step via virus specific thymidine kinase. Inhibits DNA synthesis:
Competition with deoxyGTP for DNA polymerase –> binds DNA template irreversible complex
Chain termination following incorporation into viral DNA

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

Question 54

Other Antivirals – CMV

Answer 54

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

Question 55

Common fungi of clinical interest:

Answer 55

Candida albicans
Histoplasma capsulatum
Cryptococcus neoformans
Coccidioides immitis
Aspergillus spp.
Blastomyces dermatitidis

Question 56

Azole Antifungals

Answer 56

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

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-drug interactions!!

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

Question 57

Amphotericin B

Answer 57

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)

Question 58

Echinocandins MOA, use, ADRs

Answer 58

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

Question 59

VAP – Empiric Therapy

Answer 59

Patients WITHOUT risk factors
Piperacillin-tazobactam -OR- cefepime -OR- imipenem -OR- meropenem -OR- levofloxacin

Patients WITH risk factors
Antipseudomonal B-lactam -PLUS-
Antipseudomonal fluoroquinolone -OR- aminoglycoside -OR- polymyxin
-PLUS- MRSA coverage

For those WITH ONLY MRSA risk factors
Antipseudomonal B-lactam
-PLUS- MRSA coverage