HTHSCI 2HH3 - Antimicrobials

__ / __ inpatients treated with antibiotics is harmed

1 in 5

this proportion of antibiotic regimens is not clinically indicated

19%

That's too many bro this why we have AROs smh

most common types of adverse reaction to antibiotics

- GI side effects

- MDRO infection

(these are the two most common)

prophylactic therapy

treatment given to prevent an infection from occurring

empiric therapy

treatment given when infection is suspected but the causative pathogen has not yet been identified

targeted therapy

treatment given to target the specific organism(s) causing the infection

stepwise approach to managing pts with infectious diseases

- assessment

- empiric therapy

- monitoring

- targeted therapy

- follow-up

Assessment phase of managing pts with infectious diseases

Is there an infection?

- Hx of present illness

- S+S

- rule out non infectious causes

What is the source?

- organ specific signs/symptoms?

- are there any LDA? is the pt intubated?

Is there any relevant infectious history?

- comorbidities, sick contacts, recent travel, recent hospitalization, recent ABx use, immunization history

when do we draw samples in relation to starting antibiotic therapy?

always before unless it's absolutely impossible to wait

types of samples taken for testing

- blood, urine, sputum, CSF, biopsy, nasal/rectal swabs

clinical vs surveillance/screening tests

clinical: from presumed site of infection

surveillance: checking for presence of microbe like MRSA or ESBL swabbing in the hospital on admission

what kinds of testing do we do on samples that go to the lab?

- gram stain (24h)

- organism identification, culture, PCR (usually 24-48 hours)

- antibiotic susceptibility ( >48 hours)

pillars of empiric therapy

- infection factors

- patient factors

- drug factors

patient factors to consider in empiric therapy

- demographics (age, living situation)

- PMH (comorbidities, hospitalizations, ABx use, past C+S, allergies)

- recent travel Hx, sick contacts

Drug factors: Pharmacokinetics

- ADME considerations

Drug factors: Pharmacodynamics

- what the drug does to the body

- spectrum of the drug's activity

- mechanism of action of the drug

bacteriostatic vs bactericidal

bacteriostatic:

- inhibits/slows growth

- requires a functional immune system to clear the infection

- used in less severe infections

bactericidal:

- causes bacterial death

- preferred for serious infections or immunocompromised hosts

pros of broad spectrum ABx

increased likelihood of activity against causative pathogens

(more likely to work basically)

cons of broad spectrum ABx

increased risk of promoting development of antimicrobial resistance and CDAD (yucky)

place in therapy for broad spectrum ABx

- consider for empiric therapy (before we know the causative pathogen)

- useful with some impaired host factors ex: chemo pts

- tx of multiple pathogen infections may benefit from these

pros of narrow spectrum ABx

decreased risk of antimicrobial resistance and C diff

cons of narrow spectrum ABx

decreased likelihood of activity against causative pathogen(s) if pathogen has not yet been identified

place in therapy for narrow spectrum ABx

consider for targeted therapy (since they're more specific drugs)

time dependent vs concentration dependent killing

time dependent: the longer the antibiotic concentration remains above the minimum inhibitory concentration, the better it will kill

concentration dependent: the higher the peak antibiotic concentration, the better the kill

- peak is relative to MIC

- post antibiotic effect

what is MIC?

lowest concentration of drug that is needed to inhibit bacterial growth

what is Post-Antibiotic Effect?

persistence of activity even after antibiotic concentration falls below MIC

Combining antimicrobials: Synergism

- combining antimicrobials with different mechanisms of action can produce an effect that exceeds the sum of their individual effects

Combining antimicrobials: broadened spectrum

- combining antimicrobials with different spectrums to fill gaps in coverage (make sure you get everything)

Combining antimicrobials: double coverage

- combining 2 different antimicrobials with activity against the same organism of interest:

--> increases likelihood of success

--> reduces development of resistance

Antimicrobial Resistance

- the ability of an organism to develop a tolerance to specific antimicrobials to which they were once susceptible

- this ability to evade evolves naturally over time, but is accelerated by the misuse and overuse of antimicrobials

risk factors for multi-drug resistant organism colonization/infection

- prior ABx use

- underlying disease (eg: needing hemodialysis)

- prior hospitalization (MRSA, ESBL, VRE, CRE)

- invasive procedures in healthcare settings

mechanisms of antibiotic resistance

1. modified cell wall proteins (drug can't bind)

2. plasmids with antibiotic resistant genes

3. drug inactivating enzymes

4. modification of the antimicrobial target

5. efflux pump

proportion of hospitalized pts in the USA who will develop a MDRO

1/16

yikes.

projected leading cause of death by 2050

MDRO infections. scary.

knowledge of typical organisms of normal flora of different body sites helps us to:

identify potential causative pathogens for infection to better treat immediately (ex: if we know that staph. aureus is part of the normal flora of an infected site, we'd prob want to give Vanco in the empiric therapy because MRSA is possible causative pathogen)

monitoring phase of treating infectious disease patients

- drug adverse effects

- infectious S+S (are they improving?)

- C+S of organism

- taking drug levels to analyze therapeutic concentrations

therapeutic drug monitoring

- measuring drug levels in the blood helps guide dosing to ensure effectiveness and safety of antimicrobial therapy

- timing of blood draw is an essential component

- different antimicrobials require levels to be drawn at various time points

when should TDM be done?

after the drug concentration has reached steady state (after 4-5 half lives)

Trough level

lowest serum drug concentration in the blood

- 30 minutes prior to next dose of antimicrobial

Peak level

highest serum drug concentration in the blood

- typically after full dose of antimicrobial is given

what is the risk of too low of a trough level?

increased potential for microbial resistance to the drug(s)

what is the risk of too high of a peak level?

increased potential for adverse effects and side effects of the drug(s)

targeted antimicrobial therapy

- modifying the antimicrobial regimen based on the culture and sensitivities

- frequently involves switching from broad to narrow spectrum agents

why is targeted therapy important?

- minimizes development of resistant organisms

- reduces the risk of toxic side effects

goal of targeted antimicrobial therapy?

change to an antimicrobial that has demonstrated activity against the identified organism with the NARROWEST spectrum and LEAST toxicity

follow-up stage of treatment of infectious disease

- continue to monitor for clinical improvement (S+S, side effects, drug levels)

- reassess ability to switch from IV-PO daily (are they clinically stable??)

- reassess duration of antimicrobial therapy daily (the shorter the course the better but everyone's illness is different and you don't want to rush it)

antibiotic targets

- cell wall

- cell membrane/plasma membrane

- DNA synthesis

- RNA synthesis

- Create free radicals

- Metabolic pathways

- Ribosomes

gram positive cell wall

thick peptidoglycan layer

gram negative cell wall

outer plasma membrane

thinner peptidoglycan layer

beta lactam antibiotic classes

- penicillins

- cephalosporins

- carbapenems

- monobactams (we don't talk about these here tho)

Beta Lactam MOA

- Penicillin binding proteins cross-link subunits of peptidoglycan to form the cell wall --> beta lactams bind to PBP and inhibit this cross linking, preventing cell wall synthesis

- osmotic cell lysis and death

antimicrobial properties of beta lactams:

- bactericidal

- time-dependent killing

Penicillin spectrum of activity

- NARROW

- gram +ve, few gram -ve, and oral anaerobic bacteria

Penicillin VK (PO) / Penicillin G (IV)

- commonly used for strep throat, syphilis

- PO formula best taken on empty stomach

Cloxacillin (IV/PO)

- commonly used for skin and soft tissue infections

- effective against methicillin-susceptible staph aureus (MSSA)

- PO formulation best taken on empty stomach

Amoxicillin (PO) / Ampicillin (IV)

- common uses: otitis media, outpatient community acquired pneumonia

- PO amoxicillin can be taken with food

major mechanism of resistance to beta-lactams

- inactivation of antibiotic by beta-lactamases

- beta-lactamases cause hydrolysis of the beta lactam ring --> loss of antibacterial effect

- may arise through mutations or can be encoded on plasmids that can be transferred between bacteria, increases transmission and spread of resistance

Beta-lactamase inhibitors

- used in combo with certain beta-lactam antibiotics

- inactivate beta lactamases

- very weak antibacterial activity on their own

- extend the activity of the antibiotic (broad spectrum)

- combo of ABx and beta lactamase inhibitors can increase GI side effects

common beta lactam-beta lactamase inhibitor combinations

- amoxicillin-clavulanic acid (PO/IV)

- piperacillin-tazobactam (IV) (also works against pseudomonas)

Cephalosporins

- beta lactam ABx

- broader spectrum than penicillins

- generations 3-5 are considered broad spectrum antibiotics

- different side chains give different cephalosporins different activity

Common Cephalosporins (each generation)

1st gen: Cefazolin, Cephalexin

2nd gen: Cefuroxime

3rd gen: Ceftriaxone, Ceftazidime, Cefixime

4th gen: Cefepime

5th gen: Ceftobiprole

as you go through the generations 1-5, cephalosporins have _______ coverage against gram -ve organisms

increased

Carbapenems

- beta lactam ABx

- very broad spectrum with gram positive, gram negative, and anaerobic coverage

- reserved for severe and/or drug resistant infections (works against pseudomonas (not ertapenem tho), ESBL, SPICE/SPACE organisms)

Carbapenem drugs

- meropenem

- ertapenem

- imipenem-cilastatin

All IV

SPICE/SPACE organisms

gram negative organisms that produce AmpC beta lactamases that degrade penicillins and cephalosporins

Penicillin allergies

- not as common as ppl think they are

- up to 10% of ppl think they have penicillin allergies, but less than 1% actually do have one

- allergies can be lost over time

- reaction might not be a true IgE allergy

- cross-reactivity with other beta-lactams depends on similarity of side chain structure

patients with a penicillin allergy are often prescribed ABx that are:

- less effective

- more toxic

- associated with poorer outcomes

Beta-Lactams: Adverse effects

common: GI upset, rash

uncommon: anaphylaxis, hypersensitivity responses (hepatotoxicity, blood dyscrasias, seizures)

Beta lactams and C. diff infections

- increased risk of C. diff with broad spectrum ABx and clindamycin

--> beta lactam and beta lactamase inhibitors, 3-5 gen cephalosporins, and carbapenems

monitoring for C. diff

- monitor for 3+ watery/odorous stools in a 24 hour period, abdo pain, new fever, and/or significant increase in WBCs

Vancomycin MOA

- glycopeptide antibiotic

- binds to the D-Ala-D-Ala terminus of peptidoglycan, preventing cross-linking and elongation which inhibits cell wall synthesis

Antimicrobial properties of vancomycin

- bactericidal

- time-dependent killing

spectrums of Vancomycin

- gram positive only (MRSA, Coagulase negative staphylococci)

- can't get into the walls of gram negative microbes

routes of administration of Vancomycin

PO: only for CDAD

IV: all other infections (NOT C diff)

common uses of vancomycin

infections caused by MRSA (bacteremia, osteomyelitis, endocarditis, meningitis, C diff.)

adverse effects of vancomycin

- vancomycin flushing syndrome

- thrombocytopenia

- nephrotoxicity --> (elevated serum creatinine, dec. output)

- vascular irritation

vancomycin flushing syndrome

- erythema on upper body, itching, flushing (may have hypotension)

- rate-dependent histamine mediated infusion reaction NOT an allergy

- limit infusion rate to 1g per hour

what causes vancomycin flushing syndrome

too rapid administration of vanco

when do we take vanco trough level?

30 min before 4th dose (just before steady state)

range for vancomycin therapeutic drug monitoring (generally)

10 - 20 mg/L

< 10 can lead to resistance (not enough to kill the bugs)

> 20 associated with increased nephrotoxicity

why does desired concentration of vancomycin vary?

the amount you want varies based on the infection

target concentration for vanco for most infections

10-15 mg/L

target concentration of vanco for serious, deep-seated infections caused by MRSA

15-20 mg/L

Daptomycin MOA

- penetrates cell wall and binds to the cell membrane

- non-specific porin formation

- rapid depol.

- loss of membrane potential

Daptomycin Target

cell membrane

Daptomycin antimicrobial properties

- bactericidal

- concentration dependent kill

Daptomycin spectrum

gram positive only (includes MRSA and VRE)

Daptomycin route of admin

IV only

common indications for Daptomycin

- MRSA, VRE

Daptomycin CANNOT be used for these infections:

pulmonary infections --> inactivated by surfactant in the lungs

Fluoroquinolone target

DNA synthesis

adverse effects of Daptomycin

- myalgia and myopathy

- monitor for inc. creatinine kinase and dark urine

- allergic pneumonitis (prolonged therapy > 2 weeks)

Fluoroquinolone MOA

- inhibit DNA synthesis through inhibition of DNA gyrase, topoisomerase, and irreversible chromosomal breakage

Antimicrobial properties of fluoroquinolones

- bactericidal

- concentration-dependent

Fluoroquinolones' spectrum

Broad spectrum but increasing resistance, also cover atypicals

Fluoroquinolone drugs

- ciprofloxacin

- levofloxacin

- moxifloxacin

Ciprofloxacin

more gram negative coverage (includes pseudomonas)

Levofloxacin

more gram positive coverage

Moxifloxacin

more gram positive coverage and anaerobes

"respiratory fluoroquinolones"

- levo/moxifloxacin

--> kill gram positive bacteria that cause resp. tract infections