Introduction to Antibacterial Therapy

1
Introduction to Antibacterial Therapy

• Clinically Relevant Microbiology and Pharmacology
• Edward L. Goodman, MD
• August 1, 2005

2
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
  25584-99.)
• Antibiotics are used as drugs of fear
• (Kunin CM Annals 197379555)

3
(No Transcript)
4
Antibiotic Misuse

• Surveys reveal that
• 25 - 33 of hospitalized patients receive
  antibiotics (Arch Intern Med 19971571689-1694)
  
• 22 - 65 of antibiotic use in hospitalized
  patients is inappropriate (Infection Control
  19856226-230)

5
Consequences of Misuse of Antibiotics

• Contagious RESISTANCE
• No equivalent downside to overuse of endoscopy,
  calcium channel blockers, etc.
• Morbidity - drug toxicity
• Mortality
• Cost

6
Outline

• Basic Clinical Bacteriology
• Categories of Antibiotics
• Pharmacology of Antibiotics

7
Goodmans Scheme for the Major Classes of
Bacterial Pathogens

• Gram Positive Cocci
• Gram Negative Rods
• Fastidious GNR
• Anaerobes

8
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

9
Staphylococcus aureus

• gt95 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)
• First VRSA reported July 5, 2002 MMWR
• Third isolate reported May 2004
• MICs 32 - gt128
• No evidence of spread in families or hospital

10
Evolution of Drug Resistance in S. aureus
Penicillin
Penicillin-resistant
S. aureus
1950s
S. aureus
11
MSSA vs. MRSA Surgical Site Infections(1994 -
2000)
12
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

13
Nosocomial Bloodstream Isolates
All gram-negative (21)
Other (11)
SCOPE Project
Viridans streptococci (1)
Coagulase-negative staphylococci (32)
Candida (8)
Staphylococci aureus (16)
Enterococci (11)
14
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

15
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

16
Viridans Streptococci

• Many species
• Streptococcus intermedius group
• Liver abscess
• Endocarditis
• GI or pharyngeal flora
• Most other are mouth flora cause IE

17
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

18
Gram Negative Rods

• Fermentors
• Oxidase negative
• Facultative anaerobes
• Enteric flora
• Numerous genera
• Escherischia
• Enterobacter
• Serratia, etc

• Non-fermentors
• Oxidase positive
• Pure aerobes
• Pseudomonas and Acinetobacter
• Nosocomial
• Opportunistic
• Inherently resistant

19
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
• Cant do MIC without culture
• Increasing resistance to FQ

20
Anaerobes

• Gram negative rods
• Bacteroides
• Fusobacteria
• Gram positive rods
• Clostridia
• Proprionobacteria
• Gram positive cocci
• Peptostreptococci and peptococci

21
Anaerobic Gram Negative Rods

• Produce beta lactamase
• Endogenous flora
• Part of mixed infections
• Confer foul odor
• Heterogeneous morphology
• Fastidious

22
Antibiotic Classificationaccording 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

23
Narrow Spectrum

• Active mostly against only one of the classes of
  bacteria
• gram positive glycopeptides, linezolid,
  daptomycin
• aerobic gram negative aminoglycosides,
  aztreonam
• anaerobes metronidazole

24
Narrow Spectrum
GPC GNR Fastid Anaer
Vanc ----- ----- only clostridia
Linezolid ----- ----- Only gram pos
AG ----- -----
Aztreon ----- -----
Metro ----- ----- -----
25
Narrow Spectrum
GPC GNR Fastid Anaer
Vanc ----- ----- only clostridia
Linezolid ----- ----- Only gram pos
Daptomycin ----- ----- -----
AG ----- -----
Aztreon ----- -----
Metro ----- ----- -----






26
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

27
Penicillins
Strep OSSA GNR Fastid Anaer
Pen -- /-- -- /--
Amp/ amox -- /-- /--
Ticar -- /--
Ureid --
UBLI
Carba
28
Cephalosporins
GPC non -MRSA GNR FASTID ANAER
Ceph 1 -- --
Ceph 2 --
Cepha-mycin
Ceph 3 --
Ceph 4 --
29
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

30
Pharmacodynamics

• MIClowest concentration to inhibit growth
• MBCthe lowest concentration to kill
• Peakhighest serum level after a dose
• AUCarea under the concentration time curve
• PAEpersistent suppression of growth following
  exposure to antimicrobial

31
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

32
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)

33
Higher Serum/tissue levels are associated with
faster killing

• Aminoglycosides
• Peak/MIC ratio of gt10-12 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

34
AUC/MIC AUIC

• For Streptococcus pneumoniae, FQ should have AUIC
  gt 30
• For gram negative rods where Peak/MIC ratio of
  10-12 not possible, then AUIC should gt 125.

35
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

36
Total Antibiotic Doses / Day
37
Changes in Bug/Drug Susceptibility Patterns
38
Effects on Susceptibility
39
Other Activities of CAMP

• Decrease inappropriate fluoroquinolone use
• Staff education
• Restricted reporting
• Decrease inappropriate sputum and urine cultures
• Staff education
• Laboratory disclaimer
• Decrease inappropriate vancomycin levels
• Education about unnecessary peak levels

40
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

41
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 199725240

42
Historic overview on treatment of infections

• 2000 BC Eat this root
• 1000 AD Say this prayer
• 1800s Take this potion
• 1940s Take penicillin, it is a miracle drug
• 1980s Take this new antibiotic, it is better
• ?2005 AD Eat this root