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1

Sites of Antibacterial Action

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

2

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

3

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)

4

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)

5

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

6

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

7

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

8

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

9

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

10

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)

11

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

12

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

13

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

14

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

15

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

16

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

17

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)

18

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)

19

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

20

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

21

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

22

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

23

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

24

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.

25

HAP & VAP – Diagnosis

Radiographic infiltrate that is new or progressive

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

26

HAP & VAP – Antibiogram

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

27

VAP – MDR Pathogens Risk factors:

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

28

HAP – Risk Factors

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

29

HAP – Empiric Therapy

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


30

HAP & VAP – Duration of Therapy

7-day course of antibiotics recommended

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

31

Strep Pneumo DOC

Non-resistant
Penicillin G
Amoxicillin

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

32

H Flu DOC

Non-B-lactamase producing
Amoxicillin

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

33

Mycoplasma pneumoniae DOC

Macrolide (azithromycin, clarithromycin), tetracycline (doxycycline)

34

Chlamydophila pneumoniae DOC

Macrolide (azithromycin, clarithromycin), tetracycline (doxycycline)

35

Chlamydophila psittaci DOC

doxycycline

36

Legionella spp. DOC

Fluoroquinolone, azithromycin, doxycycline

37

Enterobacteriaceae (Klebsiella, E. coli, Proteus)
DOC

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

38

Pseudomonas aeruginosa DOC

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

39

Anaerobe (aspiration): Bacteroides, Fusobacterium, Peptostreptococcus
DOC

B-lactam/B-lactamase inhibitor, clindamycin

40

Staphylococcus aureus DOC

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

Methicillin-resistant
Vancomycin or linezolid

41

Influenza virus
DOC

Oseltamivir, zanamivir

42

Pneumocystis jiroveci (P. carinii pneumonia)
DOC

Trimethoprim/sulfamethoxazole

43

Bordetella pertussis DOC

Azithromycin, clarithromycin

44

Coccidioides spp. DOC

No treatment necessary if normal host
Itraconazole, fluconazole

45

Histoplasmosis and Blastomycosis DOC

Itraconazole

46

Influenza stats and transmission

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

47

Influenza symptoms

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

48

Neuraminidase Inhibitors

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)

49

Neuraminidase Inhibitors 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

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

50

Neuraminidase Inhibitors resistance and therapeutic use

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

51

M2 Channel Blockers

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)

52

M2 Channel Blockers ADRs, resistance

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

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

53

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

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

54

Other Antivirals – CMV

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

55

Common fungi of clinical interest:

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

56

Azole Antifungals

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

57

Amphotericin B

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)

58

Echinocandins MOA, use, ADRs

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

59

VAP – Empiric Therapy

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