Introduction to Antibacterial Therapy
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Transcript Introduction to Antibacterial Therapy
Introduction to Antibacterial
Therapy
Clinically Relevant Microbiology and
Antibiotic Use
Edward L. Goodman, MD
July 2, 2007
Rationale
Antibiotic use (appropriate or not) leads to
microbial resistance
Resistance results in increased morbidity,
mortality, and cost of healthcare
Appropriate antimicrobial stewardship will
prevent or slow the emergence of resistance
among organisms (Clinical Infectious Diseases 1997; 25:584-99.)
Antibiotics are used as “drugs of fear”
(Kunin CM Annals 1973;79:555)
Antibiotic Misuse
Surveys reveal that:
– 25 - 33% of hospitalized patients receive
antibiotics (Arch Intern Med
1997;157:1689-1694)
– 22 - 65% of antibiotic use in hospitalized
patients is inappropriate (Infection Control 1985;6:226-230)
Consequences of Misuse of
Antibiotics
Contagious
RESISTANCE
– No equivalent downside to overuse of
endoscopy, calcium channel blockers, etc.
Morbidity
Mortality
Cost
- drug toxicity
Outline
Basic Clinical Bacteriology
Categories of Antibiotics
Pharmacology of Antibiotics
Goodman’s Scheme for the
Major Classes of Bacterial
Pathogens
Gram Positive Cocci
Gram Negative Rods
Fastidious GNR
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 (lower than national average)
Glycopeptide (vancomycin) intermediate (GISA)
– MIC 8-16
– Eight nationwide (one at PHD)
First VRSA reported July 5, 2002 MMWR
– Third isolate reported May 2004
– MICs 32 - >128
– No evidence of spread 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
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
Pyogenic groups
Most, but not all of the beta-hemolytic strep
S. pyogenes: Group A
S. agalactiae: Group B
S. dysgalactiae: Group C and G
Beta strept - continued
S. agalactiae (Group B)
– Peripartum/Neonatal
– Diabetic foot
– Bacteremia/endocarditis/metastatic foci
Group D (non enterococcal) = S. bovis
– Associated with carcinoma of colon
Viridans Streptococci
Many species
Streptococcus intermedius group
– Liver abscess
– Endocarditis
– GI or pharyngeal flora
Most other are mouth flora – cause IE
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!
S. anginosus Group
Most remain penicillin sensitive, but there are
increasing reports of resistance to penicillin and
cephalosporins.
Consider adding gentamicin to PenG until
sensitivities come back.
Vancomycin and clindamycin are reasonable
alternatives.
Don’t forget surgical drainage!
Streptococcus bovis
Group D, alpha or gamma hemolytic
can be misidentified as enterococci or other
viridans strep.
Biotype I and II.
GI tract, hepatobiliary system, urinary tract.
S. bovis
Bacteremias. 25-50% of bacteremias associated
with endocarditis, usually with preexisting valve
disease or prosthetic valves. Rarely osteomyelitis,
meningitis
Bacteremia caused by Biotype I is associated with
GI malignancy and endocarditis (71% and 94%).
Remain very susceptible to penicillin
Other viridans strep: mitis,
mutans and salivarius groups
Normal flora of the oral cavity. Also found
in upper respiratory, gastrointestinal and
female genital tracts.
Low virulence organisms
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
Role in intra-abdominal infection debated ( See
5/1/06 Lecture to Residents)
Gram Negative Rods
Fermentors
Oxidase negative
Facultative anaerobes
Enteric flora
Numerous genera
Non-fermentors
Oxidase positive
Pure aerobes
Pseudomonas and
Acinetobacter
– Escherischia
– Nosocomial
– Enterobacter
– Opportunistic
– Serratia, etc
– Inherently resistant
Fastidious Gram Negative
Rods
Neisseria, Hemophilus, Moraxella, HACEK
Require CO2 for growth
Neisseria must be plated at bedside
– Chocolate agar with CO2
– Ligase chain reaction (like PCR) has reduced number
of cultures for N. gonorrhea
Can’t do MIC without culture
Increasing resistance to FQ
Anaerobes
Gram negative rods
– Bacteroides
– Fusobacteria
Gram positive rods
– Clostridia
– Proprionobacteria
Gram positive cocci
– Peptostreptococci and peptococci
Anaerobic Gram Negative
Rods
Produce beta lactamase
Endogenous flora
Part of mixed infections
Confer foul odor
Heterogeneous morphology
Fastidious
Antibiotic Classification
according to Goodman
Narrow Spectrum
– Active against only one of the four classes
Broad Spectrum
– Active against more than one of the classes
Boutique
– Active against a select number within a class
Narrow Spectrum
Active mostly against only one of the
classes of bacteria
– gram positive: glycopeptides, linezolid,
daptomycin
– aerobic gram negative: aminoglycosides,
aztreonam
– anaerobes: metronidazole
Narrow Spectrum
GPC
GNR
Fastid
Anaer
++++
-----
-----
Linezolid ++++
-----
-----
Daptomy ++++
cin
AG
-----
-----
-----
only
clostridia
Only
gram pos
-----
++++
++
-----
Aztreon
-----
+++
+
-----
Metro
-----
-----
-----
++++
Vanc
Broad Spectrum
Active against more than one class
GPC and anaerobes: clindamycin
GPC and GNR: cephalosporins, penicillins,
T/S, newer FQ, GPC, GNR and anaerobes:
ureidopenicillins ± BLI, carbapenems,
tigecycline
GPC and fastidious: macrolides
Penicillins
Strep
OSSA
GNR
Fastid
Anaer
Pen
+++
--
+/--
--
+/--
Amp/
amox
Ticar
+++
--
+
+/--
+/--
++
--
++
+/--
+
Ureid
+++
--
+++
+++
++
U+BLI +++
+++
++++
+++
++++
Carba
+++
++++
++++
++++
+++
Cephalosporins
FASTID ANAER
Ceph 1
GPC non GNR
-MRSA
++++
+
--
--
Ceph 2
++
++
+
--
Cephamycin
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
Parameters of antibacterial
efficacy
Time above MIC - beta lactams, macrolides,
clindamycin, glycopeptides
24 hour AUC/MIC - aminoglycosides,
fluoroquinolones, azalides, tetracyclines,
glycopeptides, quinupristin/dalfopristin
Peak/MIC - aminoglycosides,
fluoroquinolones
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 >10 for most MRSA, >15 for
pneumonia
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 for Streptococcus pneumoniae
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.
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
Other Activities of CAMP
Try to decrease inappropriate fluoroquinolone use
– Staff education
– Restricted reporting
– Need more FTE/EHR to truly restrict FQ use
Decrease inappropriate sputum and urine cultures
– Staff education
– Laboratory disclaimer
Decrease inappropriate vancomycin levels
– Education about unnecessary (peak) levels
– Emphasis on higher Vanc troughs for MRSA
Further Activities of
CAMP/Infection Control
Monitor surgical site infections and intervene as
necessary
– Improved timing and administration of pre-op antibiotics
– clipping not shaving
– nasal decolonization?
– changing pathogens (MRSA, gram- rods)
Automated protocol-driven antibiotic prescribing
– Computerized physician order entry
– Link to Zynx Data Base
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 better
?2006 AD: 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 recent (6/6/07) Clinical
Grand Rounds on Streptococci