Antibiotics:Only Part of the Story

Gina Suh, MD/ Mayo clinic

May 10 20182019 California Orthopaedic Association Annual Meeting

May 16-19, 2019

I have no disclosures

New York Times10/6/16

New York Times10/6/16

Hatfields vs. McCoys

Hatfields vs. McCoys

Just take out the hardware!

How hard could it be?

Just suppress for life! How hard could it

be?

MSK infections

• By nature a multi-disciplinary problem• Eradication of infection may not be

best for preserving structure, function, and stability

• Preserving structure, function, and stability may not be best for eradicating the infection

• Not a lot of data – but this is getting better

The Role of the Ortho-ID Physician

TOLD FROM THE PERSPECTIVE OF AN ORTHO-ID DOC

• To give a nuanced recommendation• To understand the surgical perspective• To understand the surgical procedure• More than just bug and drug

Today’s Talk

• But first I will start with “The Bug and the Drug”

• Local delivery - doses• DAIR• Duration of antibiotics• Chronic suppression

• Empiric antibiotics• While cultures are cooking• Culture-negative PJI

• Prophylaxis• Role of oral antibiotics• Some lessons• Novel therapeutics

Staphylococcus

aureus

Methicillin-S(most)

Methicillin-R

Coagulase-negative(staph epi is most

common)

Methicillin-S

Methicillin-R(most)

Staphylococcus

aureus

Methicillin-S(most)

Methicillin-R

Coagulase-negative(staph epi is most

common)

Methicillin-S

Methicillin-R(most)

Drugs of choice:

CEFAZOLIN

VANCOMYCIN

CEFAZOLIN

VANCOMYCIN

Second Line:

Penicillin allergy:VANCOMYCIN

AKI: DAPTOMYCIN

FYI: staph lugdunensisis a Coag neg staphthat acts like staph aureus!Usually methicillin-S

streptococcus

Penicillin-S(Ex. Group A, Group B, Group C/G, anginosus)

Penicillin-R(some viridans strep, some S. pneumoniae)

streptococcus

Penicillin-S(Ex. Group A, Group B, Group C/G, anginosus)

Penicillin-R(some viridans strep, some S. pneumoniae)

Drugs of choice:

PENCILLIN OR CEFTRIAXONE

VANCOMYCIN

REMEMBER:CLINDA AND LEVODO NOT ALWAYS COVERSTREP! Ask your lab forsusceptibilities

REMEMBER:“Group A” is not the same as“alpha-hemolytic”“Group B is not the same as“beta-hemolytic”

Gram-negative rods

Pseudomonas

Non-Pseudomonas

ESBL or other high level resistance

Gram-negative rods

Pseudomonas

Non-Pseudomonas

ESBL or other high level resistance

Drugs of choice:

CEFEPIME ZOSYNCARBAPENEMS

CEFTIAXONE

CARBAPENEMSNEW DRUGS -ceftazidime/avibactam (“Avycaz”)-ceftolozane/tazobactam (“Zerbaxa”)-meropenem/vaborbactam

REMEMBER:TRY TO AVOID FLUOROQUINOLONES

Penicillin Allergy:AztreonamFluoroquinolones

Enterococcus

faecalis

Ampicillin-S(most)

Ampicillin-R

Vanco-R

faecium

Ampicillin-S

Ampicillin-R

Vanco-R(most)

Enterococcus

faecalis

Ampicillin-S

(most)

Ampicillin-R

Vanco-R

faecium

Ampicillin-S

Ampicillin-R

Vanco-R

(most)

Drugs of choice:

AMPICILLIN

VANCOMYCIN

DAPTOMYCIN

AMPICILLIN

VANCOMYCIN

DAPTOMYCIN

Other considerations:

ZOSYN

Zosyn does not work here

LINEZOLID

Remember theseDO NOT cover Enterococcus:

• Cephalosporins• Ertapenem• Meropenem • Imipenem

(But sometimes ceftriaxone used for synergy)

FUNGALCandida

Non-Candida

FUNGALCandida

Non-Candida

Drugs of choice:

Fluconazole – usually susceptibleCaspofungin – use until you have sensi’s if sick

Voriconazole – if AspergillusFluconazole or itraconazole – if coccidioidesFluconazole or itraconazole – if histoplasmosisFluconazole or itraconazole – if blastomycosis

Mycobacterial“AFB”

TB

Non-TB“NTM”

Mycobacterial“AFB”

TB

Non-TB“NTM”

Drugs of choice:

Too complicated for this slide-MUST be multi-drug regimen

Too complicated for this slide-Hundreds of different species (ex. MAC, Mycobacterium abscessus, Mycobacterium chelonae, etc”)

Antibiotic Spacer-Drug and Dose per

bag of cement

ICM Philly Page 450

Antibiotic Duration in DAIR

THE CONVENTIONAL ALGORITHM

(IDSA PJI Guidelines)

Antibiotic Duration in DAIR

HIGHLY VARIABLE

Antibiotic Duration in DAIR

HIGHLY VARIABLE

TREND TOWARD SHORTER DURATIONS

ICM PHILLY PAGE 435

Antibiotics for DAIR

GRAM NEG RODS

FUNGALAFB

• GNR: Beta-lactams or oral quinolones, durations generally shorter than GPC except Pseudomonas

• Fungal: Avoid DAIR• AFB: Avoid DAIR

Chronic Suppression

INDICATION

DURATION

PITFALLS

• Who gets chronic suppression?• Immunosuppressed• Inadequate debridement• Markers don’t normalize• Surgeon’s level of confidence• Consequences of failure

• How long?• VERY variable• My practice has been

• Staph 12-24 months• Strep 6 months• GNR 3-6 months• Candida Indefinite?

• This decision is made with YOU• Pitfalls

• They fail anyway• They fail anyway with a different and more resistant bug• C difficile – recurrent, never-ending, colostomy• Side effects: Renal failure, liver failure, lactic acidosis,

hyperkalemia and torsades, tendon rupture, tendonitis, decreased appetite, feeling lousy

Doxycycline

MY FAVORITE ANTIBIOTIC

• MSSA – highly likely (check sensi’s)

• MRSA – likely (check sensi’s)

• Strep – no

• Enterococcus – maybe (check sensi’s)

• E coli – maybe (check sensi’s)

• Pseudomonas – no

• Relatively non-toxic

• Lower rates of Clostridium difficile• Ok in renal failure

• Downsides:

• Photosensitivity

• GI upset and nausea

Empiric antibiotics after DAIR or stage-one of two stages

IMMEDIATELY POST-OP WHILE CULTURES ARE COOKING

• If they grew something in the past• Cover it!

• Broad-spectrum coverage• Vanco + Ceftriaxone• Vanco + Cefepime• Vanco + Ceftazidime• Empiric anaerobic coverage usually not needed• Avoid Vanco/Zosyn combination

• My approach: risk stratify• Start with vanco• Add Gram-negative coverage if they have risk

factors• Elderly• GI/GU issues (prostate, recurrent UTI)

Culture-negativePJI

COMMON REGIMENS

SOMETIMES IT’S SOMETHING WEIRD

• Vancomycin + ceftriaxone

• Vancomycin + cefepime

• Vancomycin + cipro

• Vancomycin + ertapenem/meropenem if high levels of MDR

• Avoid vanco/zosyn due to risk of AKI and difficulty with administration

• Unusual organisms not detectable by culture• Coxiella, Bartonella, Brucella, Mycoplasma

Extended Oral Prophylaxis Post

Re-implant

S/P RE-IMPLANT

INTRA-OP CULTURES NEG

• 2 retrospective studies and 1 RTC• Lower rates of failure in group treated with

oral prophylaxis for 3 months post-op• The failures were usually with a different

bug• There is further work to be done• Longer duration of follow up• Risk stratify

• Multiple previous failures• Retained osteomyelitis suspected• Host factors

Clin Orthop Relat Res. 2017 Jan;475(1):56-61.

OVIVA Trial

“Oral versus IV antibiotics”

A randomized control trial

• Multi-center out of UK

• 1,054 Bone and joint infections

• Randomly assigned to oral or IV 7 days

post-op or 7 days after start of abx if no

surgery indicated

• Primary endpoint: failure within 1 year

• Results: Failure 14.6% IV group 13.2% oral

group

• PO non-inferior to oral

• 1% adverse events PO group 9.3% oral

group

N Engl J Med 2019; 380:425-436

OVIVA Trial

CAVEATS

• Not a lot of staph infections

• Many streptococcal and gram-neg rods

• Not much beta-lactam use

• High levels fluoroquinolone use

• Fluoroquinolones (cipro/levo/moxi) have

been issued a black box warning for cardiac

adverse events, QT prolongation

• Clostridium difficile and tendon rupture are

major side effects

• Recommend avoidance of quinolones

N Engl J Med 2019; 380:425-436

SOME LESSONS

• Durations getting shorter and shorter• Antibiotics matter less than we like to think?• When you lift the antibiotic, the infection can recur, no matter the

duration• The debridement matters the most• But debridements are un-quantifiable• The reason why the guidelines are so conservative? They have to

“cover” all the debridements• Are debridement techniques becoming more refined?

The Real Game Changer

NEW THERAPIES

Slide modified from Paul Bollyky, with permission

Phage&biology&

Ryan,&Elizabeth&M.,&et&al.&"Recent&advances&in&bacteriophage&therapy:&how&delivery&routes,&formulaMon,&concentraMon&and&Mming&influence&the&success&of&phage&therapy."&Journal(of(Pharmacy(and(Pharmacology&63.10&(2011):&1253R1264.&&

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Bacteriophages (“phages”)

A Potential Solution: Bacteriophage Therapy

• Viruses that target bacteria• Highly specific• Low systemic dose• Low toxicity

Slide courtesy Paul Bollyky

Thanks for your attention!!!