Transcript Introduction to Antibacterial Therapy

Introduction to Antibacterial
Therapy
Clinically Relevant Microbiology and
Pharmacology
Edward L. Goodman, MD
July 21, 2003
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 ~50% of SA are hetero (methicillin)
resistant = MRSA
 Glycopeptide (vancomycin) intermediate (GISA)
– MIC 8-16
– Eight nationwide (one at PHD)

VRSA reported July 5, 2002 MMWR
– MIC >128
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%)
 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
– Non suppurative sequellae: ARF, AGN
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
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
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 has reduced number of
cultures for N. gonorrhea
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
– aerobic gram negative: aminoglycosides,
aztreonam
– anaerobes: metronidazole
Narrow Spectrum
GPC
GNR
Fastid
Anaer
++++
-----
-----
Linezolid ++++
-----
-----
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
 GPC and fastidious: macrolides
Penicillins
Strep
OSSA
GNR
Fastid
Anaer
Pen
+++
--
+/--
--
+/--
Amp/
amox
Ticar
+++
--
+
+/--
+/--
++
--
++
+/--
+
Ureid
+++
--
+++
+++
++
+++
++++
+++
++++
+++
++++
++++
++++
+BLI +++
Carba
+++
Cephalosporins
FASTID ANAER
Ceph 1
GPC non GNR
-MRSA
++++
+
--
--
Ceph 2
++
++
+
--
Cephamycin
Ceph 3
++
++
+
+++
+++
+++
+++
--
Ceph 4
+++
++++
+++
--
Boutique Antibiotics

Just like the Mall
– specialty stores
– specialty drugs

Often like the Mall – stores in search of business;
drugs in search of diseases
– Synercid – for VRE faecium, not faecalis, MRSA
– Linezolid – VRE, MRSA

ID consult needed
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

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)

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 nor 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
Total Antibiotic
Doses / Day
2.5
2
p=.001
1.5
p=.000
2000
2001
2002
1
0.5
0
Doses/Census Day
Changes in Bug/Drug
Susceptibility Patterns
30%
25%
20%
15%
10%
5%
0%
1999
2000
2001
2002
% Bug/Drug combinations having > or = 5% increase in resistance
%Bug/Drug combinations having > or = 5% decrease in resistance
Further Activities of CAMP

Decrease inappropriate fluoroquinolone use
– Staff education
– Restricted reporting

Decrease inappropriate sputum cultures
– Staff education
– Laboratory disclaimer

Decrease inappropriate vancomycin levels
– Education about unnecessary peak levels
Further Activities of CAMP

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
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
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: Take this new antibiotic, it is better
 ?2003 AD: Eat this root