Introduction to Antibacterial Therapy

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Introduction to Antibacterial Therapy

• Clinically Relevant Microbiology and Antibiotic
  Use
• Edward L. Goodman, MD
• July 2, 2007

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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)

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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)

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Consequences of Misuse of Antibiotics

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

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Outline

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

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Goodmans Scheme for the Major Classes of
Bacterial Pathogens

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

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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

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Staphylococcus aureus

• gt95 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 - gt128
• No evidence of spread in families or hospital

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

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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)
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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

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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

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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

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Viridans Streptococci

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

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Viridans group

• Anginosus sp.
• Bovis sp. Group D
• Mutans sp.
• Salivarius sp.
• Mitis sp.

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Streptococcus anginosus Group

• Formerly Streptococcus milleri or
  Streptococcus intermedius.
• S. intermedius S. constellatus S. anginosus
• Oral cavity, nasopharynx, GI and genitourinary
  tract.

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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

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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!

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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.
• Dont forget surgical drainage!

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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.

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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

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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

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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)

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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

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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

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Anaerobes

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

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Anaerobic Gram Negative Rods

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

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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

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Narrow Spectrum

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

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






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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

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

• Just like the Mall
• specialty stores (e.g., Mont Blanc store!)
• specialty drugs
• Often like the Mall stores in search of
  business drugs in search of diseases
• Synercid for VRE faecium, not faecalis, MRSA
• Tigecycline MRSA, VRE, Acinetobacter
• ID consult needed

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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

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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

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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 gt10 for most MRSA, gt15 for pneumonia

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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

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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.

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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

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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

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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

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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 2000s Take this new antibiotic, it is
  better
• ?2006 AD Eat this root

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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

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Thanks to

• Shahbaz Hasan, MD for allowing me to use slides
  from his recent (6/6/07) Clinical Grand Rounds on
  Streptococci