Introduction to Antibacterial Therapy Clinically Relevant Microbiology and Antibiotic Use Edward L. Goodman, MD July 22, 2010.

Introduction to Antibacterial Introduction to Antibacterial TherapyTherapy

Clinically Relevant Microbiology and Antibiotic Use

Edward L. Goodman, MD

July 22, 2010

OutlineOutline

Basic Clinical BacteriologyAntibiotics

– Categories– Pharmacology – Mechanisms of Resistance

Goodman’s Scheme for the Major Goodman’s Scheme for the Major Classes of Bacterial PathogensClasses of Bacterial Pathogens

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 ~60% 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

S. aureus

Penicillin

[1950s]

Penicillin-resistant

S. aureus

Evolution of Drug Evolution of Drug Resistance in Resistance in S. aureusS. aureus

Methicillin

[1970s]

Methicillin-resistant S. aureus (MRSA)

Vancomycin-resistant

enterococci (VRE)

Vancomycin

[1990s]

[1997]

Vancomycin

intermediate-resistantS. aureus (VISA)

[ 2002 ]Vancomycin-

resistantS. aureus

MSSA vs. MRSA MSSA vs. MRSA Surgical Site InfectionsSurgical Site Infections

(1994 - 2000)(1994 - 2000)Controls(n=193)

MSSA SSI(n=165)

MRSA SSI(n=121)

Death, no. (%) 4(2.1) 11(6.7) 25(20.7)

LOS aftersurg., median

5 14 23

Hosp. charges,median $

29,455 52,791 92,363

CID. 2003;36: 592-598.

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

Clin Infect Dis 1999;29:239-244

Nosocomial Bloodstream Nosocomial Bloodstream IsolatesIsolates

SCOPE ProjectSCOPE Project

Other Other (11%)(11%)

Coagulase-Coagulase-negative negative

staphylococci staphylococci (32%)(32%)

Enterococci Enterococci (11%)(11%)

All gram-All gram-negative negative (21%)(21%)

Candida Candida (8%)(8%)

Viridans Viridans streptococci streptococci

(1%)(1%)

Staphylococci Staphylococci aureusaureus (16%) (16%)

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.

Streptococcus anginosusStreptococcus anginosus GroupGroup

Formerly ‘Streptococcus milleri’ or ‘Streptococcus intermedius’.

S. intermedius; S. constellatus; S. anginosusOral cavity, nasopharynx, GI and

genitourinary tract.

S. anginosusS. anginosus Group Group

Propensity for invasive pyogenic infections ie. abscesses.

Grow well in acidic environmentpolysaccharide capsule resists phagocytosisproduce hydrolytic enzymes: hyaluronidase,

deoxyribonucleotidase, chondroitin sulfatase, sialidase

S. anginosusS. anginosus Group Group

Oral and maxillofacial infectionsBrain, epidural and subdural abscessesintraabdominal abscessesempyema and lung abscessesbacteremias usually secondary to an

underlying focus of infection. Look for the Abscess!

EnterococciEnterococci

Formerly considered Group D Streptococci now a separate genus

Bacteremia/Endocarditis Bacteriuria Part of mixed abdominal/pelvic infections Intrinsically resistant to cephalosporins No bactericidal single agent (except ?Dapto) Role in mixed flora intra-abdominal infection

trivial- therapy for 2° peritonitis need not cover

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

Fastidious Gram Negatives Fastidious Gram Negatives

Neisseria, Hemophilus, Moraxella, HACEK Require CO2 for growth

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 Increasing resistance to FQ not detected w/o culture

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

Antibiotic ClassificationAntibiotic Classificationaccording to Goodmanaccording to Goodman

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

bacteriaBroad Spectrum

– Active against more than one of the classesBoutique

– Highly specialized use– Restricted to ID physicians

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 Spectrum

Active against more than one class GPC (incl many MRSA) and anaerobes:

clindamycin GPC (not MRSA*) and GNR: cephalosporins,

penicillins, sulfonamides, TMP/Sulfa (*include MRSA), FQ

GPC (not MRSA*), GNR and anaerobes: ureidopenicillins + BLI, carbapenems, tigecycline (*MRSA), tetracyclines (*MRSA), moxiflox

GPC and fastidious: macrolides

Penicillins/CarbapenemsPenicillins/Carbapenems

Strep OSSA GNR Fastid Anaer

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

Amp/ amox

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

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

Ureid +++ -- +++ +++ ++

U+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 for at least 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 unstable 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 is 1.5 - 2, should avoid vancomycin in

favor of daptomycin, linezolid or tigecycline

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

AUC/MIC = AUICAUC/MIC = AUIC

For Streptococcus pneumoniae, FQ should have AUIC >= 30

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

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

Pathways of Common Pathways of Common Resistance MechanismsResistance Mechanisms

Impede access of drug to target– Beta lactamases: multiple classes– Aminoglycoside altering enzymes– Chloramphenicol altering enzymes– Altered porin channels – carbapenems– Efflux pumps - macrolides

Alterations in target– Altered binding proteins: MRSA, DRSP– Methylation of ribosomes: macrolides– Bypass metabolic pathways: TMP/Sulfa– Alteration in gyrases

Some Background onSome Background on EnterobacteriaceaeEnterobacteriaceae

β-lactam antibiotics (derivatives of penicillin) have long been the mainstay of treating infections caused by Enterobacteriaceae.

However, resistance to β-lactams emerged several years ago and has continued to rise.– Extended spectrum β-lactamase producing

Enterobacteriaceae (ESBLs)– Plasmid-mediated AmpC-type enzymes

Extended Spectrum Beta Extended Spectrum Beta Lactamases (ESBL)Lactamases (ESBL)

Hyper production derived from TEM beta lactamases

Predominantly in Klebsiella and E coliConfer resistance to penicillins,

cephalosporins, monobactams – Plasmids also confers R to FQ/AG– Indications for carbapenems*

Amp C Beta LactamasesAmp C Beta Lactamases Chromosomal cephalosporinases active against

– 1st - 3rd generation cephalosporins, penicillins even with BLI Constituent or Inducible Reside in periplasmic space

– Not easily detected when in low numbers SPICE organisms possess Amp C

– Serratia– Pseudomonas– Indole + Proteii– Citrobacter– Enterobacter

Indication for carbapenems* (imipenem, meropenem, ertapenem, doripenem)

The Last Line of DefenseThe Last Line of Defense

Fortunately, our most potent β-lactam class, carbapenems, remained effective against almost all Enterobacteriaceae.

Doripenem, Ertapenem, Imipenem, Meropenem

Unfortunately, “Antimicrobial resistance follows antimicrobial use as surely as night follows day”

KKlebsiella lebsiella PPneumoniae neumoniae CCarbapenemasearbapenemase

KPC is a class A -lactamase– Confers resistance to all -lactams including extended-spectrum

cephalosporins and carbapenems

Occurs in Enterobacteriaceae– Most commonly in Klebsiella pneumoniae– Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter

spp., Escherichia coli, Salmonella spp., Serratia spp.,

Also reported in Pseudomonas aeruginosa (South America)

Susceptibility Profile of KPC-Producing Susceptibility Profile of KPC-Producing K. pneumoniaeK. pneumoniae

Antimicrobial Interpretation Antimicrobial Interpretation

Amikacin I Chloramphenicol R

Amox/clav R Ciprofloxacin R

Ampicillin R Ertapenem R

Aztreonam R Gentamicin R

Cefazolin R Imipenem R

Cefpodoxime R Meropenem R

Cefotaxime R Pipercillin/Tazo R

Cetotetan R Tobramycin R

Cefoxitin R Trimeth/Sulfa R

Ceftazidime R Polymyxin B MIC >4μg/ml

Ceftriaxone R Colistin MIC >4μg/ml

Cefepime R Tigecycline S

Carbapenem resistance in Carbapenem resistance in K. pneumoniaeK. pneumoniae

NHSN Jan 2006- Sept 2007NHSN Jan 2006- Sept 2007

CLABSI CAUTI VAP Pooled

Carbapenem resistant

K. pneumoniae11% 9% 4% 8%

Hidron, A et al Infect Control Hospital Epidemiol. 2008;29:996

Geographical Distribution of

KPC-Producers

Frequent Occurrence

Sporadic Isolate(s)

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

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!?2011: Eat this root!

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

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

Jean B. Patel, PhD and CDR Arjun Srinivasan, MD, Division of Healthcare Quality Promotion at CDC for Kpc slides