Antimicrobials I

PMP Review 2013

Mark Hull
St Paul’s Hospital
February 13 2013
 Objectives
• 1. Review antimicrobial selection
principles
• 2. Review classification schema for
antimicrobials
– Mode of action
• 3. Review common antimicrobials
• 4. Clinical applications
 Rationale
• Antibiotics among the most commonly
prescribed medications

• Inadequate therapy could increase

– risk of relapse of infection

– associated clinical morbidity/mortality.

 Antibiotics save lives

Crit Care Med 2006;34:1589

 Pre-antibiotic mortality

Spellberg, B. CID 2009;49:383.

 Introduction
• Unfortunately antibiotic prescribing is often
unnecessary:
• Humans:
• • overall antibiotic prescriptions
• – unnecessary or inadequate 22–65%
• • outpatient acute respiratory
• tract infections (USA)
• – unnecessary 55%
• 2) Animals:
• • for growth promotion banned in Europe
 Antibiotic Resistance

Data from the BCCDC Antimicrobial Resistance Annual Report 2009

 Introduction
• Antimicrobial stewardship:
– Appropriate use of antimicrobials
• Selection
• Dosing
• Duration

– Appropriate step-down of antibiotics

• De-escalation of empiric coverage
• Step down to oral antibiotics
 Introduction
• Many ways to choose antibiotics:
– Empiric therapy in sick patient, aiming at most
likely/most serious organisms based on site of
infection

– Directed therapy if organism known

 Introduction – Factors influencing
antimicrobial selection
• Agent factors:
– type of bacteria suspected at that body site
– Suspected resistance patterns
• Host factors :
– Site of infection: eg. Lung vs. Brain
– pregnancy, renal failure, allergy
– immune compromise
– Antibiotic penetration eg. CNS
 Introduction – Factors influencing
antimicrobial selection cont’d
• Environmental factors:
– Nosocomial vs. Community-acquired
– Community characteristics
• Eg . Inner city
– Travel
– Exposures
• injection drug use
• Animals
• Water
 Antimicrobial concepts
• 1. Narrow Spectrum or Broad/Extended
Spectrum
– Narrow spectrum: action against a limited number of
bacteria
– Broad spectrum: activity against wide range of
bacteria
• 2. Bacteriostatic vs. Bactericidal
– Bacteriostatic drugs slow/halt replication, allow
immune system to eliminate pathogen
– Bactericidal agents kill bacteria directly
Bacteria – what do you
remember?
Gram positive Gram negative

Cocci Cocci
Staphylococcus Neisseria meningiditis
•S.areus, S.epidermidis
Streptococci Neisseria gonorrhea
•GAS, GBS etc
•S.pneumoniae
Moraxella catarrhalis
•Viridans streptococci
Enterococci
Bacilli Bacilli
Listeria, Clostridia E.coli, Klebsiella, Proteus
GI pathogens
SPACE organisms
 Antimicrobial sites of action
• 1. Cell Wall

• 2. Cell Membrane

• 3. Protein Synthesis
– 30S, 50S

• 4. Nucleic Acid

• 5. Metabolic Pathways – Folic Acid synthesis

 Antimicrobial Classification
• Classification by mode of action:

• I. cell wall synthesis inhibitors

– Penicillins, Cephalosporins, Carbapenems,
Glycopeptides
• II. Cell membrane inhibitors - Daptomycin
• III. Protein synthesis inhibitors
– Aminoglycosides, Tetracyclines, Macrolides,
Clindamycin, Linezolid
 Antimicrobial Classification
• IV. Nucleic acid agents
– Quinolones, metronidazole
• V. Anti-metabolites (Folic acid synthesis
inhibitors)
– Sulphonamides
B-lactam antibiotics
I. Cell wall agents -1. Penicillins
• Penicillins act by binding to penicillin-binding
proteins in the cell wall of bacteria
– Stop cross-linking of cell wall
– This leads to loss of wall integrity and osmotic lysis
• Cell wall target = mainly gram positive targets
• Resistance now common:
– 1. altered binding proteins (eg. S. pneumoniae)
– 2. b lactamase enzymes which cleave the antibiotic .
 I. Cell wall agents – 1.
Penicillins
• Penicillin:
• Pen V =PO
• Main role in treating gram positive
infections:
– Useful against Streptococcal species
Clinical role: MILD infections
• Group A Streptococci (Eg. GAS pharyngitis)
 I. Cell wall agents – 1. Penicillins
• Penicillin G =IV
• Time dependent
killing
– Not peak
concentration that
matters, but rather
maintaining duration
above MIC (minimum
inhibitory
concentration)
– Dosed q4hr
 I. Cell wall agents – 1. Penicillins
• Penicillin G
– Invasive Streptococcal infections
• Eg. GAS, GBS etc : bacteremia, septic arthritis,
osteomyelitis

– Step-down option for serious S. pneumoniae

infections once sensitivities confirmed
• due to resistance concerns wouldn’t use up front
 I. Cell wall agents – 1. Penicillins
• Benzathine Penicillin IM

• Long half-life

• Primary and Secondary syphilis

• Neurosyphilis requires IV Penicillin G x

14d
I. Cell wall agents – 1. Penicillin
family
• Antistaphylococcal penicillins:
• >85% resistance to Penicillin among S.aureus

• Cloxacillin (previously methicillin) IV/PO

– Drug of choice for serious S. aureus (MSSA)
infections – bacteremia, endocarditis, septic
arthritis, osteomyelitis, pneumonia etc
• Cloxacillin 2g IV q 4hr
 Cloxacillin
• Very narrow spectrum, limited additional
coverage – so used if MSSA identified

– Difficulty for cellulitis is distinguishing

Staphylococcal and Streptococcal etiology
• Therefore often use other agents for first-line
coverage
• If S.aureus cultured, could consider PO Cloxacillin
for mild infection
 I Cell Wall Agents – 1.
Penicillins
• Aminopenicillins:
– Ampicillin (IV/PO), amoxicillin PO
– Gram positive coverage: Streptococci,
Enterococci, Listeria
– But some activity against gram negative rods
(E.coli, H. influenzae, Proteus)
I Cell Wall Agents – Amoxicillin
Clinical role :
• IV Ampicillin
• Enterococcal infections (with synergistic
gentamicin for endocarditis)
• PO Amoxil
• sinus infections, otitis media
• upper respiratory infections (eg. Mild CAP,
bronchitis)
• endocarditis prophylaxis
 I Cell wall agents - Amoxicillin
If amoxicillin combined with clavulin (b
lactamase inhibitor) =broad spectrum oral
antibiotic
• Overcomes some resistance, covers gram
positives, many gram negatives and anaerobes
• Clinical role: - polymicrobial coverage
– Dental infections
– Pulmonary (mild CAP, lung abscess)
– Complicated wound infections
I. Cell wall agents – 1. Penicillin
family cont’d
Piperacillin
– Broad Spectrum antibiotic
– Gram positives, gram negatives –
(Pseudomonas) and anaerobes
• Piperacillin combined with tazobactam ( b
lactamase inhibitor) extends spectrum
even further
• Piperacillin-tazobactam (Pip-tazo, Tazocin)
 I Cell wall agents - Piperacillin
Clinical role:
• polymicrobial infection
• suspected Gram –ve resistant / unknown
source infection:
– Sepsis

– Intra abdominal infections

– Nosocomial infections
 I. Cell wall agents – 2.
Cephalosporins
• 1- 4 generations
• Derived from b lactam ring of penicillins
– Important for cross-reactivity in allergy
• Progression from 1→3 generations
– Better gram negative coverage
– Loss of gram positive coverage
(Staphylococcal coverage)
– Some species intrinsically resistant
(Enterococci, Listeria)
 I. Cell Wall Agents – 2.
Cephalosporins
• 1st generation:
• Cefazolin (Ancef) IV
• Cephalexin (keflex) PO
– Gram positives (Staphylococci, Streptococci)
– Some gram negatives: Proteus mirabilis,
E.coli, Klebsiella
• Clinical role: Skin infections (cellulitis), pre
op coverage, UTI
 I. Cell wall agents – 2.
Cephalosporins
• 2nd generation:
• Cefuroxime
• IV/PO (cefuroxime axetil)
– Lose some gram positive coverage
(S.pneumoniae best covered)
– Increased gram negatives: PEcK plus:
H.influenzae, Enterobacter (some)
• Clinical role: respiratory infections (CAP)
 I. Cell Wall Agents – 2.
Cephalosporins
• 2nd generation:
• Subgroup: cefotetan, cefoxitin (called the
cephamycins) also cover Neisseria,
anaerobes

• Therefore excellent coverage for

intrabdominal infections
– Classically used for PID, post obstetrical
infections
 Cell wall agents – 2.
Cephalosporins
• 3rd generation:
– Excellent broad gram negative coverage, some gram
positive coverage (Streptococci, some S.aureus)
• Ceftriaxone
– Penetrates Blood Brain Barrier
– Used as empiric coverage for Neisseria in meningitis
(as well as covering S.pneumoniae if not resistant to
penicillins)
– Dosed once daily for non-meningitis infections.
• Clinical: inpt CAP, Meningitis, Pyelonephritis
 Cell wall agents – 2.
Cephalosporins
• IV Ceftazidime covers Pseudomonas
– Often a component of febrile neutropenia
coverage

• PO Cefixime in adults reserved for

N.gonorrhea
 Cell wall agents – 2.
Cephalosporins
• 4th generation:
• Cefepime
– Broad-spectrum coverage against gram
positives, negatives
– Less anaerobic coverage than Pip-tazo
– Covers Pseudomonas
– Reserved for serious nosocomial infections
 I. Cell wall agents – 3.
Carbapenems
• Imipenem, Meropenem IV
– Broad spectrum coverage: gram positives,
gram negatives (Pseudomonas, ESBL
infections), anaerobes
• Clinical role:
– nosocomial infections (eg. HAP)
– polymicrobial infections
– sepsis
• May cross BBB (particularly post neurosurgery)
 I. Cell wall agents – 4.
glycopeptides
• Vancomycin IV/PO
– Bactericidal, works at step before penicillins
– Spectrum of activity: gram positive coverage
• Eg. MRSA, Coagulase negative Staphylococcus Streptococci
(Pen Resistant S.pneumoniae) Enterococci (if not able to use
penicillins)
• Clinical role:
– IV: Bacteremia, Skin and Soft tissue Infections,
osteomyelitis, joint infections
– Meningitis (S.pneumoniae)
– PO: for C. difficile
 I. Cell wall agents – 4.
glycopeptides
• Vancomycin
• Adverse effects: red man syndrome from
rapid infusion and histamine release
– Also Nephrotoxicity, neutropenia, rare
ototoxicity with long term exposure
• Follow vancomycin trough level
– Steady state after 3-5 doses
– Goal 15-20 ng/mL for MRSA infections