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