Introduction to Antibacterial Therapy: Clinically Introduction to Antibacterial Therapy: Clinically Relevant Microbiology and Antibiotic UseRelevant Microbiology and Antibiotic Use

Edward L. Goodman, MD

Hospital Epidemiologist

Core Faculty

July 11, 2013

OutlineOutline

Basic Clinical BacteriologyAntibiotics

– Categories– Pharmacology – Mechanisms of Resistance

Antibiotic Stewardship – “Pearls”

Scheme for the Four Major Classes Scheme for the Four Major Classes of Bacterial Pathogens in of Bacterial Pathogens in

Hospitalized PatientsHospitalized Patients

Gram Positive CocciGram Negative RodsFastidious Gram Negative OrganismsAnaerobes

Gram Positive CocciGram Positive Cocci

Gram stain: clusters Catalase pos = Staph Coag pos = S aureus Coag neg = variety of

species

Chains and pairs Catalase neg =

streptococci Classify by hemolysis Type by specific CHO

Staphylococcus aureusStaphylococcus aureus >95% produce penicillinase (beta lactamase) =

penicillin resistant At PHD ~53% of SA are hetero (methicillin)

resistant = MRSA (less than national average) Glycopeptide (vancomycin) intermediate (GISA)

– MIC 8-16– Eight nationwide

First VRSA reported July 5, 2002 MMWR– Seven isolates reported (5/7 from Michigan)– MICs 32 - >128– No evidence of spread w/in families or hospital

Coagulase Negative StaphCoagulase Negative Staph

Many species – S. epidermidis most common

Mostly methicillin resistant (65-85%)Often contaminants or colonizers – use

specific criteria to distinguish– Major cause of overuse of vancomycin

S. lugdunensis is rarely a contaminant– Causes destructive endocarditis

StreptococciStreptococci

Beta hemolysis: Group A,B,C etc.Invasive – mimic staph in virulenceS. pyogenes (Group A)

– Pharyngitis,– Soft tissue

Invasive TSS

– Non suppurative sequellae: ARF, AGN

Other Beta hemolytic Other Beta hemolytic

S. agalactiae (Group B)– Peripartum/Neonatal– Diabetic foot– Bacteremia/endocarditis/metastatic foci

Group C/G Streptococcus– large colony variants: similar clinical illness as GAS

plus bacteremia, endocarditis, septic arthritis– Small colony variants = Strept milleri

Viridans groupViridans group

Anginosus sp.Bovis sp.: Group DMutans sp.Salivarius sp.Mitis sp.

EnterococciEnterococci

Formerly considered Group D Streptococci now a separate genus– Bacteremia without IE does not need cidal/syngergistic

therapy– Endocarditis does need cidal/syngergistic– Bacteriuria in elderly, obstructed– Part of mixed abdominal/pelvic infections

Role in mixed flora intra-abdominal infection trivial- therapy for 2° peritonitis need not cover it

Intrinsically resistant to cephalosporins No bactericidal single agent

– For endocarditis need pen/amp/vanc plus AG– Daptomycin is cidal in vitro

Little experience in endocarditis Resistance develops (NEJM Aug 25, 2011)

Gram Negative RodsGram Negative Rods

Fermentors Oxidase negative Facultative anaerobes Enteric flora Numerous genera

– Escherischia– Enterobacter– Serratia, etc

UTI, IAI, LRTI, 2°B

Non-fermentors Pure aerobes Pseudomonas (oxidase

+) and Acinetobacter (oxidase -)– Nosocomial LRTI,

bacteremia, UTI– Opportunistic– Inherently resistant

New mechanisms of MDR emerging

Fastidious Gram Negatives Fastidious Gram Negatives Neisseria, Hemophilus, Moraxella, HACEK Growth requirements

– CO² and enrichment

Culture for Neisseria must be plated at bedside – Chocolate agar with CO2

– Ligase chain reaction (like PCR) has reduced number of GU cultures for N. gonorrhea

Can’t do MIC without culture (at reference lab only) FQ resistance 13% in 2011

– FQ not recommended for empiric Rx since 2007

AnaerobesAnaerobes

Gram negative rods– Bacteroides (gut/gu flora)– Fusobacteria (oral and gut)– Prevotella (mostly oral)

Gram positive rods– Clostridia (gut)– Proprionobacteria (skin)

Gram positive cocci– Peptostreptococci and peptococci (oral, gut, gu)

Anaerobic Gram Negative Anaerobic Gram Negative RodsRods

FastidiousProduce beta lactamaseEndogenous floraWhen to consider

– Part of mixed infections– Confer foul odor– Heterogeneous morphology– Gram stain shows GNR but routine cults negative

(My) Antibiotic Classification(My) Antibiotic Classification

Narrow Spectrum– Active against only one of the four classes of

bacteriaBroad Spectrum

– Active against more than one of the classes

Narrow SpectrumNarrow Spectrum

Active mostly against only one of the classes of bacteria– gram positive: glycopeptides, linezolid,

daptomycin, telavancin– aerobic gram negative: aminoglycosides,

aztreonam– anaerobes: metronidazole

Narrow SpectrumNarrow SpectrumGPC GNR Fastid Anaer

Vanc ++++ ----- ----- only clostridia

Linezolid ++++ ----- ----- Only gram pos

Dapto/Telavancin

++++ ----- ----- -----

AG ----- ++++ ++ -----

Aztreon ----- +++ + -----

Metro ----- ----- ----- ++++

BROAD SPECTRUMBROAD SPECTRUMPenicillins/CarbapenemsPenicillins/Carbapenems

Strep OSSA GNR Fastid Anaer

Pen ++++ -- +/-- -- +/--

Amp/ amox

++++ -- + +/-- +/--

Ticar ++ -- ++ +/-- +

Pip +++ -- +++ +++ ++

Pip/BLI

++++ ++++ +++ +++ ++++

Carba ++++ ++++ ++++ ++++ ++++

CephalosporinsCephalosporins

GPC non -MRSA

GNR FASTID ANAER

Ceph 1 ++++ + -- --

Ceph 2 ++ ++ + --

cefoxitincefotetan

++ ++ + +++

Ceph 3 +++ +++ +++ --

Ceph 4 +++ ++++ +++ --

PharmacodynamicsPharmacodynamics

MIC=lowest concentration to inhibit growth MBC=the lowest concentration to killPeak=highest serum level after a dose AUC=area under the concentration time

curvePAE=persistent suppression of growth

following exposure to antimicrobial

Pharmocodynamics: Dosing Pharmocodynamics: Dosing for Efficacyfor Efficacy

Blo

od L

evel

Time

Peak

MIC

Trough

Parameters of antibacterial Parameters of antibacterial efficacyefficacy

Time above MIC (non concentration killing) - beta lactams, macrolides, clindamycin, glycopeptides

24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin

Peak/MIC (concentration dependent killing) - aminoglycosides, fluoroquinolones, daptomycin,

Time over MICTime over MIC For beta lactams, should exceed MIC > 50% of

dose interval Higher doses may allow adequate time over MIC For most beta lactams, optimal time over MIC can

be achieved by continuous infusion (except temperature labile drugs such as imipenem, ampicillin)

For Vancomycin, evolving consensus that troughs should be >15 for most serious MRSA infections, especially pneumonia and bacteremia– If MRSA MIC >= 2 and patient responding slowly or

poorly, should change vancomycin to daptomycin, linezolid or tigecycline

– Few THD MRSA have MIC >1

Higher Serum/tissue levels are Higher Serum/tissue levels are

associated with faster killingassociated with faster killing Aminoglycosides

– Peak/MIC ratio of >10-12 optimal – Achieved by “Once Daily Dosing”– PAE helps

Fluoroquinolones – 10-12 ratio achieved for enteric GNR

PAE helps– not achieved for Pseudomonas – Not always achieved for Streptococcus pneumoniae

Daptomycin– Dose on actual body weight

FQ AUC/MIC = AUICFQ AUC/MIC = AUIC

For Streptococcus pneumoniae, FQ should have AUIC >= 30

For gram negative rods where Peak/MIC ratio of 10-12 not possible, then FQ AUIC should >= 125

For MRSA, vancomycin AUIC needs to be >=400. Not easily achieved when MIC >=2.

A Brief Overview of A Brief Overview of Antimicrobial ResistanceAntimicrobial Resistance

ESKAPE Organisms (mechanism) ESKAPE Organisms (mechanism)

Enterococcus faecium VRE (Van A)Staphylococcus aureus MRSA (MEC A)Klebsiella pneumoniae (ESBL – KPC)Acinetobacter baumanii (KPC – NDM1)Pseudomonas aeruginosa(AmpC, KPC,

NDM-1)Enterobacter species (AmpC)

Mechanisms of Antimicrobial Resistance in Mechanisms of Antimicrobial Resistance in BacteriaBacteria

FC Tenover Amer J Med 2006;119: S3-10FC Tenover Amer J Med 2006;119: S3-10

Folic acid synthesis

ß-lactams & Glycopeptides (Vancomycin)

50 50 5030 30 30

DNA

mRNA

Ribosomes

PABA

DHFA

THFA

Cell wall synthesis

DNA gyrase

Quinolones

Protein synthesis inhibition

Protein synthesis inhibitionTetracyclines

Protein synthesis mistranslation

Macrolides & Lincomycins

Cohen. Science 1992; 257:1064

DNA-directed RNA polymerase

Rifampin

Aminoglycosides

Sulfonamides

Trimethoprim

Mechanisms of Antibiotic ResistanceMechanisms of Antibiotic ResistancePM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J PM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J

1998;317: 657-6601998;317: 657-660

Interplay of Interplay of ββ lactam antibiotics and bacteria lactam antibiotics and bacteriaPM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J PM Hawkey, The origins and molecular basis of antibiotic resistance. Brit Med J

1998;317: 657-6601998;317: 657-660

Bad Beta Lactamases (for Bad Beta Lactamases (for dummies like me)dummies like me)

ESBL– Klebsiella and E coli– Require carbapenems although for UTI Pip/tazo might

work– Not clear how transmissible but use Contact Isolation

AMP C– SPICE organisms

Inducible/derepressed chromosomal beta lactamases– Requires carbapenems when AMP C expressed– Do not require Contact Isolation unless associated

plasmid transmits MDR

ReallyReally Bad Beta Lactamases Bad Beta Lactamases

Carbapenem Resistant Enterobacteraciae (CRE)– Resistant to everything but colistin and sometimes

tigecycline

New Delhi Metalloproteinases (NDM)– Pseudomonas and enterobacteraciae– Resistant to all but colistin

These patients require Contact Isolation and Cohorting

Antibiotic Use and ResistanceAntibiotic Use and Resistance

Strong epidemiological evidence that antibiotic use in humans and animals associated with increasing resistance

Subtherapeutic dosing encourages resistant mutants to emerge; conversely, rapid bactericidal activity discourages

Hospital antibiotic control programs have been demonstrated to reduce resistance

Antibiotic ArmageddonAntibiotic Armageddon

“There is only a thin red line of ID practitioners who have dedicated

themselves to rational therapy and control of hospital infections”

Kunin CID 1997;25:240

When to Cover for MRSAWhen to Cover for MRSASevere purulent SSTINecrotizing pneumonia/empyemaCentral line associated(Known MRSA carriers?)

Go To Drug = Vancomycin

Is Vancomycin Needed for every Is Vancomycin Needed for every patient with SSTI? patient with SSTI?

CID 2011:1-38CID 2011:1-38

When to Cover for PseudomonasWhen to Cover for Pseudomonas

Severe COBPD/bronchiectasis– Frequent ABX– Steroid dependent– Known airway colonization

Neutropenic septic leukemic(Burn patients)

Is Pseudomonas Coverage Needed Is Pseudomonas Coverage Needed for Every Diabetic Foot Infection?for Every Diabetic Foot Infection?

CID 2012; 54 (12):132-173CID 2012; 54 (12):132-173

Historic overview on treatment of Historic overview on treatment of infectionsinfections

2000 BC: Eat this root1000 AD: Say this prayer1800’s: Take this potion1940’s: Take penicillin, it is a miracle drug1980’s – 2000’s: Take this new antibiotic, it

is a bigger miracle!?2014: Eat this root!

Thanks toThanks to

Shahbaz Hasan, MD for allowing me to use slides from his 6/6/07 Clinical Grand Rounds on Streptococci

Eliane S Haron, MD for allowing me to use the “Eat this root” slide

Terri Smith, PharmD for collecting data from the Antibiotic Stewardship Program