Antibioti c Update Paul D Simmons, MD, FAAFP - PowerPoint Presentation

Slide1

Antibioti

c Update

Paul D Simmons, MD, FAAFP

Faculty Physician

St. Mary’s Family Medicine Residency Program

Grand Junction, ColoradoSlide2

Objectives

1. Discuss newly approved antibiotics, using the STEPS approach – safety, tolerability, efficacy, price, and simplicity.2. Discuss how to counsel patients on the proper use of antibiotics and why they may not be necessary.

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There is nothing intrinsically “powerful,” “strong,” or “big gun” about an antibiotic. The use of these terms is a reliable marker (sensitivity and specificity 99% in my hands) that the speaker knows nothing about antibiotics. They are marketing concepts, no more helpful than the phrase “new and improved.” I think, without data in this instance, that antibiotics are not used as chemicals to kill organisms in a specific body space. Rather, they are magical talismans that are used to ward off evil spirits. Instead of possession by demons we have infection by

Pseudomonas

; and instead of exorcism we give

Zosyn

. The words may have changed, but the thinking behind it remains unchanged.

- Mark Crislip, MD

Infectious Disease SpecialistCreator of the “Infectious Disease Compendium” app

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AES Question

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https://commons.wikimedia.org/wiki/File:Circle-question-blue.svg#/media/File:Circle-question-blue.svgSlide5

Which of the following is an aerobic Gram-negative bacillus often feared in healthcare-associated pneumonia?

Bacteroides

Moraxella

Listeria

Pseudomonas

Peptostreptococcus

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Gram-positive cocci are the most common infectious agents in which of the following body areas?

Urinary tract

Skin and soft tissue

Abdomen

Respiratory tract

Both 1 and 3

Both 2 and 4

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Which of the following antibiotics is bacteriostatic?

Clindamycin

Cephalexin

Vancomycin

Metronidazole

Rifaximin

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The Road Map

1. Review and Overview of Antibiotics

2. New antibiotics

- ceftazidime/avibactam

-

ceftolozane

/tazobactam - new abx for MRSA

3. Changes to old antibiotics

-

rifaximin

- shorter courses for abdominal infection

- beta-lactams for severe sepsis

4. Flu vaccine update (not an antibiotic!)

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Map of Williamsburg, Virginia (1782), in the public domain, from Wiki Commons.Slide9

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The Organisms

Aerobic

Gram positive cocci

Streptococcus

Staphylococcus

EnterococcusGram positive bacilliListeria

Corynebacterium

Anaerobic

Gram positive cocci

Peptococcus

Peptostreptococcus

Gram positive bacilli

ClostridiaSlide10

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The Organisms

Aerobic

Gram negative cocci

Moraxella

Neisseria

Gram negative bacilliE. coliProteus

Shigella

Klebsiella

Haemophilus

Pseudomonas

Anaerobic

Gram negative cocci

(NONE)

Gram negative bacilli

Bacteroides

FusobacteriumSlide11

Choosing Empiric Therapy

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Site of Infection

Likely Organisms

Urinary tract

GNB

,

Staph

,

Enterococcus

Skin and soft tissue

Staph

(

inc

MRSA)

,

Strep

Abdomen

GNB

,

Enterococcus

, Anaerobes (e.g.,

Bacteroides

)

Respiratory tract

Strep

,

Haemophilus

,

Moraxella

, Mycoplasma,

Legionella

,

ChlamydiaSlide12

Choosing Empiric Therapy

Is the organism a colonizer, a contaminant, a commensal, or a pathogen?

Host factors: age, hepatic and renal function, immune status, allergies…

Do you want bacteriostatic or bactericidal?

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Bacteriostatic vs Bactericidal

Bacteriostatic

Macrolides

Clindamycin

Tetracyclines

Sulfonamides

Linezolid

Chloramphenicol

Streptogramins

Bactericidal

Penicillins

Cephalosporins

Monobactams

Carbapenems

Vancomycin

Aminoglycosides

Fluoroquinolones

Lipopeptides

Metronidazole

Rifamycins

RifaximinSlide14

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Bacteriostatic vs Bactericidal

Bacteriostatic

Macrolides

Clindamycin

Tetracyclines

Sulfonamides

Linezolid

Chloramphenicol

Streptogramins

Bactericidal

Penicillins

Cephalosporins

Monobactams

Carbapenems

Vancomycin

Aminoglycosides

Fluoroquinolones

Lipopeptides

Metronidazole

Rifamycins

Rifaximin

MRSASlide15

The best tool you have (next to culture and sensitivities)?Your local

antibiogram!

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There are SO many cephalosporins!

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Barriers to PracticeSlide17

A Brief Diversion into the Oft-Confusing World of

Cephalosporins

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Cephalosporins

1st gen

2nd gen

3rd gen

4th gen

Cefazolin (Ancef)

Cephalexin (Keflex)

Cefadroxil (Duricef)

Cefuroxime (Zinacef)

Cefuroxime axetil (Ceftin)

Cefoxitin (Mefoxin)*

Ceftriaxone (Rocephin)

Cefixime (Suprax)

Cefdinir (Omnicef)

Ceftazidime (Fortaz)*

Cefepime (Maxipime)

Ceftaroline (Teflaro)

Gm +

Gm -

+++

+

++

++

++

+++

+++

+++

*

Anaerobic

*

Pseudomonas

5

th

gen

++++

++

*

MRSA Coverage

Slide courtesy of Dr Tim Brown, Akron General Medical Center and Northeast Ohio Medical UniversitySlide19

Cephalosporins

1st generation

2nd generation

3rd generation

4th generation

5

th

generation

Surgical prophylaxis

Skin and soft tissue

Uncomplicated UTI

URI?, LRTI

Abdominal infections/prophylaxis

URI

esp

oral?, LRTI, meningitis,

gonorrhea

Reserved for drug-resistant

Infections; multi-organism

CAP, Skin and soft tissue, ESBL

Slide courtesy of Dr Tim Brown, Akron General Medical Center and Northeast Ohio Medical UniversitySlide20

Fluoroquinolone Update

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Fluoroquinolones are heavily marketed, and many of us learned to reach for ciprofloxacin for UTIs, or to levofloxacin for sinusitis…

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Barriers to PracticeSlide22

AES Question

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https://commons.wikimedia.org/wiki/File:Circle-question-blue.svg#/media/File:Circle-question-blue.svgSlide23

Which of the following is NOT a known adverse effect of fluoroquinolones?

QT prolongation on EKG

Tendonitis and tendon rupture

Peripheral neuropathy

Retinal detachment

None of the above are adverse effects of FQs

All of the above are adverse effects of FQs

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FDA Warns About Fluoroquinolones

November 2015: A joint panel of the FDA states that FQs need much stronger warnings re:

Risk of tendonitis and tendon rupture

QT prolongation

Peripheral neuropathy

Panel met to discuss use of FQs for acute bacterial sinusitis, acute exacerbation of COPD and uncomplicated UTIs.

The panel “voted overwhelmingly that the benefits and risks for the systemic fluoroquinolone antibacterial drugs

do not support the current labeled indications

for the treatment of ABS (unanimous), ABECB-COPD (2 yes, 18 no, 1 abstention), or uncomplicated urinary tract infection (1 yes, 20 no).”

Take Away:

We should stop reflexively reaching for ciprofloxacin for UTIs, or levofloxacin for AECOPD and sinusitis!

These are not benign drugs.

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Medscape Medical News, 6 Nov 2015

"

Grünes

skelett

" by Unknown -

veränderte

Version von

dem

hier

. Licensed under Public Domain via Wikimedia Commons.Slide25

Fluoroquinolones and Retinal Detachment

Studies conflict about FQ and retinal detachment risk.This French study included 28,000 patients undergoing retinal detachment surgery over 3 years.

Case-crossover design: FQ use in 10 d prior to surgery vs control period (61-180 d prior to surgery).

AdjOR

1.5 for retinal detachment in those who recently used FQ

Only individual FQ associated with this risk was levofloxacin

Note: RR was increased, but AR increase was tiny - only 1 in 1000 retinal detachment patients had FQ exposure.

JAMA

Ophthalmol

2016 April; 134:415

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New Antibiotics

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Ceftazidime / Avibactam (2015)

Ceftazidime: a third-generation cephalosporinActive against GN enteric

organisms

Little to no activity against

GP

or

anaerobesAvibactam is a non-beta-lactamase beta-lactamase inhibitor

Increases activity vs.

Pseudomonas

and ESBL (+) organisms

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Image of Pseudomonas via CDC, public domain, via Wiki CommonsSlide28

Ceftazidime / Avibactam

Where might this be useful?Complicated UTI or abdominal infections with KPC (Klebsiella

pneumoniae

carbapenemase

) – producing organisms.

What does it cost?

Around $900 a dayMy take? The second cephalosporin/BLI IV combo in 2 years. Expensive, niche drug for the emerging problem of ESBL organisms.

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Pharmacology

Class Cephalosporin antibiotic/beta-lactamase

inhibitor

Route Intravenous

Formulation 2.5-g single-use vials

(2 g ceftazidime/0.5 g avibactam)

Usual adult dosage 2.5 g (infused over 2 hours) every 8 hours

Dosage in renal impairment

CrCl

31-50 mL/min: 1.25 g every 8 hours

CrCl

16-30 mL/min: 0.94 g every 12 hours

CrCl

6-15 mL/min: 0.94 g every 24 hours

CrCl

≤5 mL/min: 0.94 g every 48 hours

Metabolism

Ceftazidime: none

Avibactam: none

Excretion

Ceftazidime: urine (80-90% unchanged)

Avibactam: urine (97% unchanged)

Half-life

Ceftazidime: ~3 hours

Avibactam: ~2.5 hours

Adapted from The Medical Letter, 25 May 2015, Issue 1469Slide29

Ceftolozane / Tazobactam (2015)

Ceftolozane

: similar to third-generation

cephalosporins

, but with a side chain that enhances anti-

Pseudomonal

activity.Tazobactam: familiar from piperacillin/

tazobactam

, improves activity against most ESBL organisms.

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Image of molecular structure of

ceftolozane

via Wiki Commons user Edgar181, public domain. Not actual size.Slide30

Ceftolozane / Tazobactam

When might this be useful?

Similarly to ceftazidime/avibactam,

ceftolozane

/

tazobactam

is for complicated UTIs and intra-abdominal infections. It is also only available IV.What does it cost? Around $2000 for a 7-day course.

My take? A niche drug for inpatient

treatement

of complicated, ESBL-producing UTIs and abdominal infections, especially

Pseudomonas

.

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Table from Med Lett Drugs

Ther

. 2015 Mar 2;57(1463):31-3Slide31

New Weapons Against MRSA

Standard treatment: vancomycinAlternatives:

daptomycin

, clindamycin, linezolid, (

televancin

,

ceftaroline)For simpler infections, I&D + SMX/TMP or doxycycline usually effectiveTwo new drugs:

Dalbavancin

(2014)

– similar to vancomycin and

televancin

(2011), an IV

lipoglycopeptide

; no QT prolongation; given in two 30-min infusions, one week apart. A mere $4500 for the course.

Tedizolid

phosphate (2014)

– similar to linezolid,

PO

and IV

oxazolidinone

; once a day for 6 days (linezolid BID), no CBC monitoring needed. $1410 for the course.

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Here’s the Bad News about New Antibiotics

Deak D et al. Ann Intern Med 2016 May 31In 2010, IDSA started the «10 by 20» initiative – 10 new antibiotics by 2020 in response to threat of MDR bacteria8 new abx approved by the FDA since 2010

But...all but one (a new TB drug, bedaquiline) are «me-too» drugs, members of already-established classes

The authors’ sad conclusion:

“recently approved antibiotics have generally been lacking in biological innovation or public health importance.”

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Some Updates For Old Antibiotics

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Rifaximin

What we have for IBS-D: loperamide,

alosetron

(5-HT

3

antagonist), fiber, and recently approved

eluxadoline (mu-opioid agonist).Rifaximin: minimally absorbed, thought to change gut microbiome, ?reduce inflammation and motilityTARGET-1 and -2 trials: n = 1260 randomized to placebo or

rifaximin

550mg TID x 2 weeks, followed for 10 more weeks

41% vs 32% reported “adequate relief” of IBS symptoms for 2 of 4 weeks after treatment, and benefit persisted (but declined) over 10 week follow-up

S/E similar to placebo; C diff, elevated CPK and

myalgias

rare

Recommended dose: 550mg TID x 14 days; can be repeated x 2 if symptoms recur.

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Read more about it: The Medical Letter issue 1474, 3 Aug 2015.Slide35

Are you killing people by not giving antibiotics for their URI?

We all agree (in theory) that we shouldn’t be giving so many antibiotics for URIs, but we fear the rare terrible complications (peritonsillar abscess, pneumonia, meningitis).

British study of a database of >600 primary care practices, tallying 45 million patient-years!

Compared practices with the lowest (38%) and highest (65%) median rate of prescribing abx for URIs, and followed outcomes.

In the lowest-prescribing group:

4 / 10,000 additional cases of pneumonia

1 / 10,000 additional cases of peritonsillar abscess

Boiled down, in a clinic with 7000 patients, reducing abx prescribing by 10% would result in 1 additional pneumonia and 1 peritonsillar abscess over 10 years.

Flaws: no patient-level data (vaccinations, comorbidities, etc.)

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Gulliford MC et al. BMJ 2016 Jul 4Slide36

Beta-lactams for Severe Sepsis

The question: Is it more effective to give beta-lactams via continuous or intermittent infusion

in severe sepsis?

The study:

25 ICUs, n = 422 patients receiving pip/

taz

, ticar/clav or meropenem

; randomized to continuous vs intermittent 30-min infusions

The findings:

No difference in ICU-free survival at 28 days or at 90 days. Limitations: <20% bug identified; no pharmacokinetic monitoring

Take-Away:

Both continuous and intermittent beta-lactam administration works for severe sepsis

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Read more about it:

Dulhunty

JM et al. Am J

Respir

Crit

Care Med 2015 Dec 1. 

Chastre

J and

Luyt

C-E. Am J

Respir

Crit

Care Med 2015 Dec 1.

"Clinicians in Intensive Care Unit" by

Calleamanecer

- Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.Slide37

Antibiotic Use for Hospitalized Patients with Community-Acquired Pneumonia

A systematic review of published literature about antibiotic use in hospitalized pts with CAPAntibiotic administration within 4-8 hours of hospital arrival resulted in lower mortality (earlier is better)

Beta-lactam vs beta-lactam + macrolide studies are conflicting; recent RCT showed beta-lactam alone is non-inferior (optimal

abx

therapy is still surprisingly controversial)

(

N Engl J Med 2015; 372:1312)Transitioning from IV to PO antibiotics when patients “clinically stable” (using objective criteria) shortens stay without adverse outcomes

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Lee JS et al. JAMA 2016 Feb 9.Slide38

Flu Vaccine Update(I know it’s not an antibiotic.)

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AES Question

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https://commons.wikimedia.org/wiki/File:Circle-question-blue.svg#/media/File:Circle-question-blue.svgSlide40

True or False: Severe egg allergy is a contraindication to receiving the inactivated, injected influenza vaccine.

True

False

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Flu Vaccine and Egg Allergy

Background: In 2012, the CDC recommended pts with mild egg allergy (hives) get the injected inactivated flu vaccine, and pts with severe allergy get it from a clinician experienced in treating anaphylaxis

The Study:

n = 780 children and adolescents from UK allergy centers, 35% had had anaphylaxis from egg exposure, 57% had asthma or recurrent wheezing

The Findings:

NO SYSTEMIC ALLERGIC REACTIONS OCCURRED, and only 1% had mild local reactions

Take-Away:

We should no longer use “egg allergy” as a reason not to give the flu vaccine

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"

Fluzone

vaccine extracting" by Jim

Gathany

- This media comes from the Centers for Disease Control, public domain.

Read more about it:

Turner PJ et al. BMJ 2015 Dec 8. Greenhawt M. BMJ 2015 Dec 9. Slide42

Best Practice Recommendations

Do the hard work of thinking about (i

) the likely organism(s); (ii) host factors; and (iii) local resistance patterns in choosing an empiric agent.

Generally, as you progress through cephalosporin generations, you get more

Gram negative

coverage. Choose your

cephalosporins wisely and reserve the newer generations!Fluroquinolones

should not

be used as first-line agents in bacterial sinusitis, AECOPD nor UTIs.

There are two new cephalosporin/BL combos and two new drugs for MRSA on the market.

Rifaximin

is probably useful for IBS-D (though pricey).

Consider shorter courses (4d) of antibiotics for abdominal infections once the source is controlled.

Give injectable flu vaccine to your egg-allergic patients!

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