Transcript Introduction to Antibacterial Therapy

Introduction to Antibacterial
Therapy
Clinically Relevant Microbiology and
Antibiotic Use
Edward L. Goodman, MD
July 22, 2010
Outline

Basic Clinical Bacteriology
 Antibiotics
– Categories
– Pharmacology
– Mechanisms of Resistance
Goodman’s Scheme for the Major
Classes of Bacterial Pathogens

Gram Positive Cocci
 Gram Negative Rods
 Fastidious Gram Negative Organisms
 Anaerobes
Gram 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 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
Evolution of Drug
Resistance in S. aureus
Penicillin
Methicillin
Methicillin-resistant
Penicillin-resistant
S. aureus
S. aureus (MRSA)
[1970s]
[1950s
S. aureus
]
[1997]
Vancomycin
[1990s]
Vancomycin-
resistant
S. aureus
Vancomycin
[ 2002 ]
intermediateresistant
S. aureus
(VISA)
Vancomycin-resistant
enterococci (VRE)
MSSA vs. MRSA
Surgical Site Infections
(1994 - 2000)
Controls MSSA SSI MRSA SSI
(n=193) (n=165)
(n=121)
Death, no. (%)
4(2.1)
11(6.7)
25(20.7)
LOS after
surg., median
5
14
23
52,791
92,363
Hosp. charges, 29,455
median $
CID. 2003;36: 592-598.
Coagulase 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
Nosocomial Bloodstream
Isolates
All gramnegative
(21%)
Viridans
streptococci
(1%)
Other
(11%)
SCOPE Project
Coagulasenegative
staphylococci
(32%)
Candida
(8%)
Enterococci
(11%)
Staphylococci
aureus (16%)
Clin Infect Dis 1999;29:239-244
Streptococci

Beta hemolysis: Group A,B,C etc.
 Invasive – mimic staph in virulence
 S. pyogenes (Group A)
– Pharyngitis,
– Soft tissue
 Invasive
 TSS
– Non suppurative sequellae: ARF, AGN
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 group

Anginosus sp.
 Bovis sp.: Group D
 Mutans sp.
 Salivarius sp.
 Mitis sp.
Streptococcus anginosus
Group
Formerly ‘Streptococcus milleri’ or
‘Streptococcus intermedius’.
 S. intermedius; S. constellatus; S. anginosus
 Oral cavity, nasopharynx, GI and
genitourinary tract.

S. anginosus Group
Propensity for invasive pyogenic infections ie.
abscesses.
 Grow well in acidic environment
 polysaccharide capsule resists phagocytosis
 produce hydrolytic enzymes: hyaluronidase,
deoxyribonucleotidase, chondroitin
sulfatase, sialidase
S. anginosus Group

Oral and maxillofacial infections
 Brain, epidural and subdural abscesses
 intraabdominal abscesses
 empyema and lung abscesses
 bacteremias usually secondary to an
underlying focus of infection.
 Look for the Abscess!
Enterococci







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 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

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
Anaerobes



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
Rods

Fastidious
 Produce beta lactamase
 Endogenous flora
 When to consider
– Part of mixed infections
– Confer foul odor
– Heterogeneous morphology
– Gram stain shows GNR but routine cults
negative
Antibiotic Classification
according to Goodman

Narrow Spectrum
– Active against only one of the four classes of
bacteria

Broad Spectrum
– Active against more than one of the classes

Boutique
– Highly specialized use
– Restricted to ID physicians
Narrow 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 Spectrum
GPC
GNR
Fastid
Anaer
++++
-----
-----
Linezolid ++++
-----
-----
Dapto/Te ++++
lavancin
AG
-----
-----
-----
only
clostridia
Only
gram pos
-----
++++
++
-----
Aztreon
-----
+++
+
-----
Metro
-----
-----
-----
++++
Vanc
Broad 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/Carbapenems
Strep
OSSA
GNR
Fastid
Anaer
Pen
++++
--
+/--
--
+/--
Amp/
amox
Ticar
++++
--
+
+/--
+/--
++
--
++
+/--
+
Ureid
+++
--
+++
+++
++
U+BLI +++
++++
++++
+++
++++
Carba
++++
++++
++++
++++
++++
Cephalosporins
FASTID ANAER
Ceph 1
GPC non GNR
-MRSA
++++
+
--
--
Ceph 2
++
++
+
--
cefoxitin ++
cefotetan
Ceph 3
+++
++
+
+++
+++
+++
--
Ceph 4
++++
+++
--
+++
Pharmacodynamics

MIC=lowest concentration to inhibit growth
 MBC=the lowest concentration to kill
 Peak=highest serum level after a dose
 AUC=area under the concentration time
curve
 PAE=persistent suppression of growth
following exposure to antimicrobial
Pharmocodynamics: Dosing for
Efficacy
Peak
MIC
Trough
Time
Parameters of antibacterial
efficacy

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 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
associated 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 = 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.
DNA gyrase
Quinolones
Cell wall synthesis
DNA-directed RNA
polymerase
Rifampin
ß-lactams &
Glycopeptides
(Vancomycin)
DNA
THFA
Trimethoprim
mRNA
Ribosomes
Folic acid
synthesis
DHFA
50
30
50
30
50
30
Protein
synthesis
inhibition
Macrolides &
Lincomycins
Sulfonamides
PABA
Protein synthesis
mistranslation
Aminoglycosides
Cohen. Science 1992; 257:1064
Protein synthesis
inhibition
Tetracyclines
Pathways of Common
Resistance 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 on
Enterobacteriaceae
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
Lactamases (ESBL)

Hyper production derived from TEM beta
lactamases
 Predominantly in Klebsiella and E coli
 Confer resistance to penicillins,
cephalosporins, monobactams
– Plasmids also confers R to FQ/AG
– Indications for carbapenems*
Amp 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 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”
Klebsiella Pneumoniae
Carbapenemase

KPC is a class A b-lactamase
– Confers resistance to all b-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
K. 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
K. pneumoniae
NHSN Jan 2006- Sept 2007
CLABSI CAUTI VAP
Carbapenem
resistant
K. pneumoniae
11%
9%
4%
Pooled
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 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
infections

2000 BC: Eat this root
 1000 AD: Say this prayer
 1800’s: Take this potion
 1940’s: Take penicillin, it is a miracle drug
 1980’s – 2000’s: Take this new antibiotic, it
is a bigger miracle!
 ?2011: Eat this root!
Antibiotic 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 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