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Antimicrobial Overview-Background Information

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Objectives

•  Learn the bugs (a very brief review) •  To learn the characteristics of

antimicrobials – Mechanism of action – Pharmacokinetics – Spectrum of activity – Adverse drug effects – Any other fascinating tidbits

•  Learn how to get the drugs to kill the bugs

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Bugs

Bacteria

Gram + Aerobes

Gram - An aerobes

Cocci Bacilli Spiro

Viruses

Fungi

Parasites Protozoa Worms

Atypicals

Mycoplasma

Chlamydia

Others

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The difference between Gram (+) and Gram (-) organisms

Gram Positive

•  Gram-Stain –  Purple

•  Shape –  Cocci –  Bacilli

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Gram Positive Cocci

•  Staphylococcus – aureus

•  Methicillin-sensitive (MSSA) •  Methicillin-resistant (MRSA) •  Vancomycin-intermediate (VISA) {fairly rare} •  Vancomycin-resistant (VRSA) {very rare}

– epidermidis •  Methicillin-resistant (MRSE)

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Gram Positive Cocci

•  Streptococcus –  pneumoniae

•  Penicillin resistant streptococcus pneumoniae (PRSP) –  pyogenes (Group A, GABHS) –  agalactiae (Group B, GBS) –  Viridans Streptococci

•  Enterococcus

–  Faecalis, faecium •  Vancomycin-resistant enterococcus (VRE)

–  Usually facecium

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Gram Positive Bacilli

•  Corynebacterium diphtheriae

•  Propionibacterium acnes

•  Listeria monocytogenes

Gram Negative

•  Gram-Stain –  Red

•  Shape –  Coccobacilli –  Cocci –  Bacilli

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Gram negative cocci

•  Neisseria – meningitidis – gonorrhoeae

•  Moraxella catarrhalis (cocco-bacillus)

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Gram negative bacilli (bacilli=rods)

•  Proteus – vulgaris (indole-positive) – mirabilis, M morganii (indole-negative)

•  E. coli •  Enterobacter species •  Acinetobacter species •  Klebsiella pneumoniae •  Serratia marcescens

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Gram negative bacilli Enteric bacteria

•  Salmonella typhi

•  Shigella sp.

•  Campylobacter jejuni

•  E. coli (0157:H7)

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Gram negative bacilli Pseudomonads

•  Pseudomonas aeruginosa

•  Stenotrophomonas maltophilia

•  Aeromonas hydrophilia

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Gram negative bacilli

•  Haemophilus influenzae

•  Legionella pneumophilia

•  Gardnerella vaginalis

•  Helicobacter pylori

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Anaerobes

•  Bacteroides fragilis

•  Clostridium difficile

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Encapsulated organisms

•  Streptococcus pneumoniae

•  Haemophilus influenzae

•  Neisseria sp.

Common Bacteria by Site of Infection Mouth Peptococcus Peptostreptococcus Actinomyces

Skin /Soft Tissue S aureus S pyogenes S epidermidis

Abdomen E. coli Proteus Klebsiella Enterococcus Bacteroides

Urinary Tract E. coli Proteus Klebsiella Enterococcus Staph saprophyticus

Bone & Joint S. aureus S. epidermidis Streptococci N. gonorrhoeae Gram negative bacilli

Upper Respiratory S pneumoniae H influenza M catarrhalis S pyogenes

Meningitis S pneumoniae N meningitidis H influenza Group B strep E coli Listeria

Lower Respiratory (CAP) S pneumoniae H influenza K pneumoniae Legionella pneumophilia Mycoplasma Chlamydia

Lower Respiratory (HAP) P aeruginosa Enterobacter Serratia S aureus Acinetobacter 17

Antimicrobials and Resistance

How Antibiotics Work •  Cell wall destruction •  Increased cell wall

permeability •  Protein synthesis

inhibition •  DNA/RNA disruption •  Antimetabolites

How Bad Bugs React: •  Production of

inactivating enzymes •  Changing the target

site •  Decreased uptake

into bacterial cells •  Synthesis of

antagonizing compounds

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Ribosomes

(Proteins)

2. Penetrate Cell

3. Reach Target and Kill

Organism

Bacterium

Requirements for Antimicrobial Activity

Antibiotics

1. Reach site of infection

Porin Proteins

PBPs DNA gry Topo IV

Feldstein TJ 00 19

Four Main Types of Resistance

• Decreased Permeability • Drug Efflux • Drug Inactivation • Altered Target

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Ribosomes

(Proteins)

Mechanisms of Resistance

Bacterium

Porin Channels (Gram-negatives)

Antibiotics

Antibiotics Porin channels closed or decreased number

Example: Pseudomonas aeruginosa

DNA gry Topo IV

Feldstein TJ 00 21


Ribosomes

(Proteins)

Feldstein TJ 00


Bacterium

Antibiotics

Examples: 1. S. pneumoniae vs. Macrolides and Quinolones 2. E. coli vs. Quinolones

Efflux Pump

DNA gry Topo IV

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Ribosomes

(Proteins)


Bacterium

Antibiotics

Examples: - Beta-lactamase (H. flu, M. cat) - Aminoglycoside modifying enzymes (Pseudomonas)

Enzymes

DNA gry Topo IV

Feldstein TJ 00 23

Ribosomes

(Proteins)

2. Penetrate Cell

3. Reach Target and Kill

Organism

Porin Proteins

Pencillin-Binding Proteins (PBPs)

(β-lactams)

DNA gry Topo IV

Feldstein TJ 00

DNA Gyrase Topoisomerase IV



Ribosomal Mutation (Macrolides)

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Altered Target

Antibiotic X Target Receptor Antibiotic X

Antibiotic X Altered Antibiotic X Target Receptor 25

Terms

•  Bacteriostatic

•  Bacteriocidal

•  Colonization

•  Synergy

•  Antibiogram

•  Prophylaxis

•  Empiric

•  Targeted

•  Definitive 26

Antibiotic Activity and Effectiveness are determined by...

•  MIC (minimal inhibitory concentration) –  in vitro potency of the drug

•  Pharmacokinetics –  “What the body does to the drug” –  Absorption, Distribution, Metabolism, Elimination

•  Pharmacodynamics –  “What the drug does to the body/organism” –  Time-kill profile

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General Definitions •  The minimum inhibitory concentration (MIC)

is the minimum concentration of the antibacterial agent in a given culture medium below which bacterial growth is not inhibited

•  The therapeutic index is the plasma or tissue toxic concentration divided by the MIC.

•  Post-antibiotic effect (PAE) means the continued inhibition of the organism for a period of time after the concentration of the antimicrobial agent has dropped below the MIC.

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•  Definition: The lowest antibiotic concentration required to visually inhibit bacterial growth following an overnight incubation.

Susceptibility Testing Minimal inhibitory concentration (MIC)

Broth: 104-105 CFU/ml (pathogen)

0.25 ug/ml 0.5 ug/ml 1 ug/ml 2 ug/ml 4 ug/ml 8 ug/ml 16 ug/ml Antibiotic Conc

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Susceptibility Testing •  Determining the MIC

– Methods: •  Organism is placed in broth solution

–  Turbidity = microbial growth –  Adding antibiotic à no turbidity

•  Agar solution •  Epsilometer strip (E-test) •  Automated systems

– Micro lab uses CLSI guidelines to determine whether a organism is “susceptible”, “intermediate”, or “resistant”

Zone of inhibition

correlates to MIC

CLSI= Clinical and Laboratory Standards Institute 30

MIC Breakpoints

•  CLSI Guidelines – Different for each organism for each antibiotic! –  Susceptible –  Intermediate –  Resistant

•  Can concentration be met in the body? –  At infection site?

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MIC Drug Concentrations

0

1

2

3

4

5

6

7

8

9

Control

2x MIC

4x MIC

Time in Hours

Log

Col

ony-

Form

ing

Uni

ts /

mL

General Understanding that Drug Concentration greater than 4-5 fold

higher than the MIC, lack of increased organism killing for TIME DEPENDENT

Antibiotics 32

PAE

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MICs and Pharmacodynamics…in English

•  Pharmacodynamics – Can we achieve MIC-achieving abx

concentration in body safely? •  Too much drug à toxicities

– Typical killing characteristics of a drug: •  Time above MIC (ex. Beta-lactams) •  AUC/MIC •  Peak/MIC

34 AUC= area under the curve

Another view-Pharmacokinetic/pharmacodynamic parameters

affecting abx potency

http://www.antimicrobe.org/h04c.files/history/PK-PD%20Quint.pdf 35

Antibiograms: The Susceptibility “Report Card”

•  Represents how often a drug has activity against the organism (as a percentage)

•  Useful for empiric therapy •  Consider:

–  Which agents have highest likelihood of being active –  Which agent will penetrate site of infection –  Are there patient factors that exclude the drug of choice

(allergies, renal toxicity risk, etc.)

Gentamicin Piperacillin/ Tazobactam

Cefepime Ciprofloxacin

Pseudomonas aeruginosa 80 89 91 82 Klebsiella pneumoniae 92 95 96 90

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Antibiotic Activity

•  Killing Properties – Time-dependent killing – Concentration-dependent killing

•  Mechanism of Action – Generalizations but different between most

classes

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Time Dependent or Concentration-Dependent Killing

•  Concentration-dependent Killing

•  Increasing the dose, increases the bactericidal effect

–  Quinolones –  Aminoglycosides –  Azalides (eg. azithro) –  Streptogramins –  Glycylcylines –  Oxazolidinones

•  Time Dependent (aka Concentration-independent Killing)

•  There is an upper limit of 4-5

times the MIC in which concentration-dependent effect is seen; further increases produce little additional killing –  β -lactams –  Macrolides –  TMP/SMX

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Bacteriologic Killing Profile: β-Lactams (PCNs, Cephs, & Penems) &

Vancomycin

Time-dependent Drug Time Above MIC

Time of Drug Concentration Above MIC

§  MIC

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Bacteriologic Killing Profile: Aminoglycosides, Fluoroquinolones

Concentration-dependent Concentration of Drug at Target Site

Peak Concentration of Drug

§  MIC

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Antimicrobial Stewardship

•  Involves the optimal selection, dose, and duration of an antibiotic

•  Minimal unintended consequences – Emerging resistance – Adverse drug events (ex. C. diff) – Cost

•  Goal: improve patient care and healthcare outcomes

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Antimicrobials Principles •  De-escalation/streamlining

– After cultures and susceptibilities return, guide clinician in transitioning from broad spectrum to narrow spectrum

•  Dose optimization via PK/PD – Ex. Levofloxacin 750mg daily for Community

Acquired Pneumonia (adjust for renal fxn) •  IV to PO switch

– Reduces line-related infection – Can decrease length of stay – Cost savings 42

Other Tips •  Clarify infection vs colonization vs

contaminants – Ex. UTIà was urine culture from catheter?

Was culture only yeast with a catheter in place? Does patient have UTI symptoms?

– Ex. Tracheal aspirates à ICU pts are frequently colonized; other signs/symptoms are helpful

•  WBC? Fever? New infiltrate on chest x-ray?

•  If “broadening therapy,” draw new cultures before antibiotics administered 43

45 Slide from Nancy Baily, Pharm.D. Sep 2005

Carbapenems, Monobactams, Vancomycin

Clindamycin, Linezolid, Synercid, Tigecycline

Colistin Metronidazole

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Drugs

Beta-Lactam Antibiotics Pencillins Cephalosporins Monobactams Cephamycins Carbapenems

Tetracyclines Fluoro-

quinolones

Aminoglycosides Macrolides

Sulfonamides

Miscellaneous

Vancomycin

Metronidazole

Bacitracin Polymyxin

Chloramphenicol

Linezolid

β-Lactams

•  Penicillins

•  Cephalosporins

•  Carbapenems

•  Monobactams

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Meet the Beta-Lactam All-Stars Penicillins Cephalosporins Carbapenems “Natural Penicillins” 1st- generation Imipenem

Meropenem Doripenem

Penicillin G & Penicillin V Cefazolin & Cephalexin Anti-staph penicillins 2nd-generation Nafcillin & Dicloxacillin Cefuroxime Ertapenem Aminopenicillins Cefotetan & Cefoxitin Ampicillin & amoxicillin 3rd-generation Monobactams Ampicillin/sulbactam & Amoxicillin/clavulanate

Ceftriaxone & Cefotaxime Aztreonam Ceftazidime

Antipseudomonal penicillins 4th-generation Piperacillin/tazobactam Cefepime

“5th-generation” Ceftaroline

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β-lactams •  Mechanism of action

–  Interferes with cell wall synthesis – Binds penicillin-binding proteins (PBPs)

•  Leads to inhibition of peptidoglycan synthesis

•  Class adverse effects –  hypersensitivity –  rare seizures (at high doses) –  interstitial nephritis –  bone marrow suppression (rare)

•  Time-dependent bacteriocidal activity

Penicillins Cephalosporins Carbapenems Monobactams

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The Penicillins

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The Beta-lactam Ring

Natural Penicillins

Penicillin G Pen VK (PO)

Gram-positive Pen-susc S. aureus Pen-susc S. pneumoniae Streptococci Enterococcus

Gram-Negative Neisseria

Anaerobes (Above the diaphragm) Clostridium

Other Treponema pallidum Syphilis

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Penicillinase-Resistant Penicillins

Nafcillin Oxacillin

Methicillin* Dicloxicillin (PO)

Gram-positive Methicillin-susceptible Staph. aureus Viridans streptococci (less than natural penicillins) NO enterococci

•  Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins

•  Preferred for beta-lactamase + MSSA

*Methicillin-no longer available 53

Aminopenicillins Ampicillin Amoxicillin (PO)

Gram-positive Pen-susc S. aureus Group streptococci Viridans streptococci Enterococcus sp Listeria monocytogenes

Gram-Negative Proteus mirabilis Salmonella Shigella E. coli H. influenza

•  Developed to increase activity against gram-negatives •  Major uses:

–  Endocarditis (usually given in combo with gent) –  Empiric:

•  Meningitis (Listeria)- Ampicillin IV for age <3 or >50 years

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Aminopenicillin + β-lactamase inhibitor

Ampicillin/sulbactam (IV) Amoxicillin/clavulanate (PO)

Gram-positive S. aureus (not MRSA) Anaerobes Bacteroides sp. (excellent)

Gram-Negative (β-lactamase producers) H. influenza E. coli Proteus sp. Klebsiella sp.

•  Developed to overcome resistance from β-lactamase producing gram-negatives

•  Sulbactam – beta lactamase inhibitor •  Clavulanate – beta lactamase inhibitor

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Extended-spectrum Penicillins + β-lactamase inhibitor Piperacillin/tazobactam

Ticarcillin/clavulanate Gram-positive S. aureus (Not MRSA) Anaerobes Excellent activity Bacteroides sp.

Gram-Negative (β-lactamase producers) H. influenza E. coli Proteus mirabilis Salmonella Shigella P. Aeruginosa Enterobacter Stenotrophomonas (Ticarcillin/clavulanate) •  Added Pseudomonas coverage

•  Major uses: –  Intra-abdominal infections –  Pneumonia (Piperacillin/Tazobactam)

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Beta-lactamase Inhibitors •  Sulbactam, Clavulanate (clavulanic acid), and

Tazobactam •  Binds to and inhibits beta-lactamases which

destroy penicillins •  Piperacillin/tazobactam- Zosyn (IV only) •  Ampicillin/sulbactam-Unasyn (IV only) •  Ticarcillin/clavulanate (IV only) •  Amoxicillin/Clavulanate acid-Augmentin (oral

only)

Beta-Lactamase Inhibitors •  Tazobactam

–  Piperacillin/tazobactam (IV) •  Wide range of G(+)

– MSSA, Strep spp, enterococcus •  Wide range of G(-)

– Pseudomonas, Serratia, Enterobacter •  Anaerobes: great for Bacteroides fragilis •  Can prolong infusion (3-4hrs) to increase T>MIC; q8h •  Renal adjustment needed •  Uses: Pseudomonas infections, intra-abdominal, febrile

neuptropenia, healthcare associated pneumonia (HCAP)

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Mechanism of Action •  Inhibit bacterial cell wall synthesis

–  binding to 1 or more of the penicillin-binding proteins (PBP)

•  PBP are a normal part of many bacteria

–  inhibits final transpeptidation step in peptidoglycan synthesis

•  Peptidoglycans is major component of bacterial cell wall –  bacteria lyse due to ongoing activities of cell wall

autolytic enzymes –  cell wall assembly arrested

•  Bacteriocidal

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•  Failure to penetrate the outer membrane – Alterations in PBPs

• Production of beta-lactamases

Resistance: Beta-Lactamase

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Spectrum of Activity - summary •  Natural

–  mostly Gram (+) –  some anaerobes

•  PCNase-resistant –  Staphylococci –  Streptococci

•  Aminopenicillins –  mostly Gram (+) –  some Gram (-) –  some anaerobes

•  Extended Spectrum –  Gram (+), but not as

good as other groups –  Excellent Gram (-)

coverage –  Anaerobes

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Pharmacokinetics •  Oral Bioavailability of

20-60% •  Half-lives of all

penicillins are short, typically 30-60 min –  require q4-6h dosing

•  Excellent tissue distribution

•  < 80% protein binding, except for PRPs (>90%)

•  Eliminated primarily by renal (Glomerular Filtration and Tubular Secretion) except for oxacillin and nafcillin, which are extensively metabolized via the liver –  Note: there is no need

to dose adjust oxacillin or nafcillin in patients with renal impairment

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Indications •  Pneumonia •  Group B streptococcal disease prevention •  URI •  Bronchitis (acute/chronic) •  Otitis media •  Sinusitis •  Pharyngitis •  UTI •  Skin/tissue infections •  Meningitis •  Endocarditis •  H.Pylori infections •  Dog and cat bites (mostly amoxillin/clav acid)

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Adverse Effects

•  IgE-mediated Hypersensitivity –  Anaphylaxis –  Accelerated (early)

skin rashes •  “Late” skin rashes •  Serum Sickness Rxn •  Drug-induced fever

•  Hematologic effects •  Diarrhea and CDAD* •  Neuromuscular

effects •  Nephropathy •  ADEs specific to

certain penicillins •  Cross sensitivity to

cephs, carbapenems –  Important to know rxn

*CDAD=clostridium difficile associated disease

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The Cephalosporins

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Beta Lactam ring

Cephalosporins

•  Disrupt bacteria cell wall

•  Divided into 4 or 5 generations

•  Antibacterial activity varies between generations and agents

•  Resistance (drug inactivation vs. altered target)

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1st Generation Cephalosporins

Injectables •  Cefazolin

(Ancef®, Kefzol®) •  Cephalothin

(Keflin®) •  Cephapirin

(Cefadyl®) •  Cephradine

(Velosef®)

Orals •  Cephalexin

(Keflex®) •  Cefadroxil

(Duricef®)

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1st Generation Cephalosporin coverage includes...

•  Activity similar to PRP vs staph and strep – Most activity against gram positives

•  Limited gram-negative coverage, including E. coli, Proteus mirabilis, and Klebsiella (many strains are now resistant)

•  No significant differences in spectrum of activity among the first-generation cephalosporins

•  Susceptible to β-Lactamases

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2nd Generation Cephalosporins

Injectables •  Cefuroxime (Zinacef®,) •  Cefamandole

(Mandol®) •  Cefonicid (Monocid®) •  Cefmetazole

(Zefazone®) •  Cefoxitin (Mefoxin®) •  Cefotetan (Cefotan®)

Orals •  Cefaclor (Ceclor®) •  Cefuroxime axetil (Ceftin ®) •  Cefprozil (Cefzil®) •  Loracarbef (Lorabid®)


•  Cefotetan, Cefoxitin, Cefuroxime, Loracarbef, Cefaclor, Cefprozil –  Loracarbef & Cefprozil Susceptible to β-

Lactamases

•  Gram-positive organisms –  Variable activity against Staphylococci –  No Enterococcus coverage

•  Broader Gram-negative coverage –  No Pseudomonas coverage

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Cephalosporin Generations

•  Gram(+) Coverage –  1st: +++ –  2nd: ++ –  3rd: +

•  Gram (-) Coverage –  1st: + –  2nd: ++ –  3rd: +++

•  Anaerobic Coverage –  1st: 0 –  2nd: +++ –  3rd: +/-

Notice the pattern!

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2nd Generation Cephs cover...

•  Slightly lower activity against S. aureus when compared to 1st gen

•  Increased activity against Gram (-) such as E. coli, Proteus, and Klebsiella, as well as, Haemophilus influenzae

•  Cephamycins (cefmetazole, cefoxitin, and cefotetan) also add additional coverage against anaerobes such as Bacteroides fragilis


•  Cephamycins – Cefoxitin – Cefotetan

•  Gram-negative organisms •  Gram-positive organisms

–  No Enterococcus coverage •  Additional anaerobic coverage

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3rd Generation Cephalosporins Injectables •  Cefotaxime (Claforan®) •  Ceftriaxone (Rocephin®) •  Ceftizoxime (Cefizox®) •  Cefoperazone (Cefobid®) •  Ceftazidime (Fortaz®) •  Cefepime (Maxipime®)

–  considered by some to be a “fourth” generation cephalosporin

Orals •  Cefixime (Suprax®) •  Ceftibuten (Cedax®) •  Cefdinir (Omnicef®) •  Cefpodoxime

(Vantin®)

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Bacterial Coverage of the 3rds...

•  Excellent Gram (-) coverage •  Two categories: those which kill

Pseudomonas aeruginosa (cefoperazone, ceftazidime, cefepime) and those that do not

•  Ceftazidime has poorest activity against Gram (+)

•  Cefotaxime has best activity vs Gram (+) •  Ceftizoxime has best activity vs anaerobes

3rd Generation Cephalosporins •  Ceftazidime, Ceftriaxone, Ceftizoxime,

Cefotaxime, Cefixime

•  Cefixime –  susceptible to β-Lactamases

•  Ceftriaxone and Cefotaxime –  Fine for community-acquired infections –  ?Nosocomial

•  Ceftazidime –  Pseudomonas-be aware of resistance; 2gm IV Q8hr –  Weak Gram + coverage –  Susceptible to Amp C and ESBLs

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4th Generation Cephalosporins

•  Cefepime – Others investigational only – Like ceftriaxone and ceftazidime together

•  Does have Pseudomonas coverage – Decent Gram + coverage, less affected by

type 1 mutations – ?Susceptibility to β-Lactamases – Dosing

•  1gm IV Q12hr - 2gm IV Q8hr

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1st-4th generation Cephalosporins Do Not cover….

•  Methicillin-resistant Staphylococcus aureus or epidermidis

•  Enterococci •  Listeria monocytogenes •  Legionella pneumophilia •  Stenotrophomonas maltophilia

“5th” generation Cephalosporin

•  Injectable •  Ceftaroline (Teflaro®) •  Not allowed to call themselves “5th” per

FDA

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5th generation-approved 11/10 •  Ceftaroline (Teflaro®) •  Community-acquired bacterial pneumonia

(CABP) caused by: –  Streptococcus pneumoniae, Staphylococcus aureus

(MSSA only) ,Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli

•  Acute bacterial skin and skin structure infections (ABSSSI) caused by: –  Staphylococcus aureus (including MRSA),

Streptococcus pyogenes,Streptococcus agalactiae, Escherichia coli,Klebsiella pneumoniae, Klebsiella oxytoca

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Ceftaroline •  Quite active against most Gram-positive cocci including

MRSA, Coag-neg Staph (methicillin resistant), and PNSP. •  MRSA activity is due to high binding affinity for PBP2a. •  Gram-negative activity resembles ceftriaxone •  The drug is poorly active vs. P. aeruginosa and Acinetobacter •  Ceftaroline-demonstrates good-to-excellent activity against

Gram-positive anaerobic pathogens (Clostridium & Peptostreptococcus) but poor activity against Gram-negative anaerobic pathogens, particularly members of the B. fragilis group.

•  Has been described as a short half-life version of ceftriaxone with souped-up Gram-positive activity including MRSA. Dosage: 600mg IV q12hrs for adults > 18

–  Adjust dosage in renal patients

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Mechanism of Action of Cephalosporins

•  Inhibit bacterial cell wall synthesis –  binding to 1 or more of the penicillin-binding proteins

(PBP) –  Inhibits the final transpeptidation step in

peptidoglycan synthesis –  bacteria eventually lyse due to ongoing activities of

cell wall from autolytic enzymes –  cell wall assembly is arrested

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• Decreased penetration of cell wall

• Altered target site •  Inactivation by beta-lactamases

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Pharmacokinetics-Cephs

•  Widely distributed – 3rd generation agents cross the Blood Brain

Barrier to treat meningitis •  All 1st & 2nd, and most 3rd (except

cefoperazone, and ceftriaxone) are eliminated renally

•  None of the cephalosporins are bound to plasma proteins to an extent that they will displace highly protein-bound drugs

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Indications

•  Otitis media •  Sinusitis •  STDs •  UTIs •  Skin/Tissue •  Pneumonia •  Meningitis

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Adverse Effects •  Hypersensitivity

similar to PCNs –  cross-sensitivity:

0-10% –  most with PCN allergy

can take cephalosporin

•  Thrombocytopenia •  Liver function tests •  CDAD

–  3rds are most common cause

•  Ceclor Reaction •  Pseudocholelithiasis

–  Ceftriaxone

•  Disulfiram-like Rxn –  NMTT side chain –  Cefamandole,

cefotetan, cefmetazole •  Hypoprothrombinemia

–  NMTT side chain

Cephalosporin Clinical Pearls

•  Many oral and IV formulations •  No Coverage for Enterococcus •  3rd Generation Cephalosporins are

susceptible to ESBL producing organisms •  Some 2nd Generation Cephalosporins are

effective for Gram (–) organisms AND Anaerobic organisms

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Cephalosporin Summary 1st Gen. 2nd Gen. 3rd Gen. 4th Gen.

Cephalexin Cefoxitin Ceftazidime Cefepime

Cefazolin Cefotetan Ceftriaxone

Cefaclor Cefuroxime Ceftizoxime

Cephalothin Loracarbef Cefotaxime

Cefprozil Cefixime

Increasing Gram-positive Coverage – No Cephalosporin covers Enterococcus

Increasing Gram-negative Coverage

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The Carbapenems

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Representative antibiotics

•  Imipenem/cilastatin (Primaxin®) •  Meropenem (Merem®) •  Ertapenem (Invanz®) •  Doripenem (Doribax®)

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Mechanism of Action-Carbapenems

•  Inhibits bacterial cell wall synthesis by binding to PBPs

•  Preferentially binds to PBP 1 and PBP 3 •  Highly resistant to degradation via

beta-lactamases

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Mechanisms of Resistance-Carbapenems

• Reduced binding to PBPs • Decreased penetration of

periplasmic space •  Inactivation via

carbapenemases

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Spectrum of Activity-Imipenem, Doripenem, Meropenem

•  “Gorilla” cillin –  the broadest spectrum

of activity of all available antibiotics

•  Excellent coverage of staphylococci and streptococci

•  Don’t use vs MRSA, MRSE, enterococci, or Listeria

•  Stenotrophomonas maltophilia is innately resistant - produces carbapenemase!

•  Highly active against all obligate anaerobes

•  Pseudomonas aeruginosa often becomes resistant during therapy

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Resistance to carbapenems •  Organisms from the Enterobacteraciae family

are increasingly producing carbapenemases that are rendering carbapenems ineffective.

•  Original name was KPCs because it was most often isolated from Klebsiella pneumonia.

•  Name has changed to CRE to represent carbapanem resistant enterobacteraciae (not just from Klebsiella any more)

•  Note other MDROs can be resistant to carbapenems as well

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When should carbapenems be used??? – Imipenem, doripenem, meropenem

•  Do not use indiscriminately!!!!

•  Monotherapy for infections in which other antibiotics have failed

•  Empiric therapy in critically ill, immunocompromised patients if resistant bugs anticipated

•  Must renal dose all •  Will see many institutions

use only one

•  Directed therapy against organisms known to be resistant to other agents

•  In general, imipenem should not be used in combination with other antibiotics –  no synergy with AGs –  strong inducer of beta-

lactamases

97

Ertapenem (Invanz®) •  Indicated for the following moderate to

severe infections: – Diabetic foot infections without osteomyelitis – Complicated intra-abdominal infections – Complicated skin/skin structure infections – Community-acquired pneumonia – Acute pelvic infections – Complicated urinary tract infections –  Prophylaxis of Surg. Site infxn following

elective colorectal surgery – No activity against Pseudomonas

98

Pharmacokinetics – Imipenem/cilastatin •  Eliminated almost exclusively via

glomerular filtration and tubular secretion •  It is very important to dose adjust in

patients with renal dysfunction because of a particularly nasty ADR (which we’ll discuss in more detail shortly)

•  Cilastatin prevents the degradation by renal peptidase dehydropeptidase-1 in the proximal tubules of the kidneys –this enzyme will hydrolyze imipenem

99

Adverse Effects - Imipenem •  Gastrointestinal

–  most common (n/v/d) –  rapid infusion may

increase •  Neurologic

–  SEIZURE! •  CNS Disease •  High dose in elderly and

renal dysfunction •  concurrent theophylline •  If carbapenem treatment

required-meropenem may be an option (renal dose)

•  Other –  hypersensitivity

•  rash •  pruritus •  urticaria •  drug fever •  cross-reactivity with

other beta-lactams –  Leukopenia –  Thrombocytopenia

100

Indications-Imipenem •  Lower RTI

–  S. aureus, acinetobacter sp, enterobacter sp, E.coli, H. flu, Kleb sp, and Serratia marcescens

•  Intra-abdominal infections

•  Skin and skin structure

•  Gynecologic

•  Septicemia –  E. faecalis, S. aureus,

enterobacter sp, E.coli, H. flu, Kleb sp, P. aeruginosa, serratia sp. And bacteriodes sp. Including B frag.

•  Bone and bone joint •  Polymicrobic

101

Doripenem (Doribax®)

•  Indications –  Comp. Intra-abdominal –  Comp. UTI (inc. pyelo)

•  Dosing –  Adj. in renal patients

•  Adverse Reactions –  Hypersensitivity

•  Similar to other carbapenems

–  CDAD (Clostridium difficile associated disease)

•  Drug Interactions –  Valproic Acid (VA)

•  Reduces conc. Of VA which could precipitate seizure activity

–  Probenecid •  Reduces renal

clearance of doripenem resulting in increased doripenem concentration

102

Meropenem (Merem®)

•  Indications –  Comp. intra-abdominal –  Comp. skin and skin

structure infections

•  Dosing –  Adjust in renal patients

•  Adverse Reactions –  Headache, rash,

diarrhea, anemia –  CDAD

•  Drug Interactions –  Probenecid: avoid use –  Decrease level of:

•  Valproic acid •  Typhoid vaccine

103

Aztreonam (Azactam®) •  The only marketed

monobactam •  Binds preferentially to PBP

3 of Gram (-), so only activity

•  Gram(-) coverage comparable to Aminoglycosides (AGs & 3rds gen. cephalosporins)

•  Probably most suited as an alternative to AGs in patients with AG-R bugs or high-risk for AG Tx

•  Most common ADEs are GI symptoms, mild skin rashes, and reversible elevations of LFTs

•  Eliminated primarily via the kidneys

•  May be inactivated by extended-spectrum beta-lactamases

•  No cross-sensitivity with penicillins

•  IV, no oral form

104

Clindamycin Cleocin®

105

Mechanism of Action

•  Reversibly binds to the RNA of the 50S ribosomal subunit – prevents peptide bond formation –  inhibiting protein synthesis

106


•  Altered or mutation of target site

•  Inactivation by bacterial esterases

107

Spectrum of Activity

•  Aerobic gram positive cocci – staph aureus, staph epidermidis, streptococci,

pneumococci •  Anerobic gram negative bacilli

– bacteroides •  Anaerobic gram positive bacilli

– propionibacterium 108

Pharmacokinetics

•  Bioavailability ~90% •  Both IV and PO forms •  Metabolized by liver •  Not renally dosed (not renally excreted) •  Does not cross blood brain barrier •  Is a derivative of lincomycin so classifed

as Lincosamides •  Wide distribution-CNS penetratation

109

Adverse Effects

•  GI effects – Warning for pseudomembranous colitis

•  Hypersensitivity rxns •  Jaundice •  Transient neutropenia, eosinophilia

110

Vancomycin (Glycopeptide)

111

Mechanism of Action

•  Interferes with cell wall synthesis – disrupts cross-linkage of peptidoglycan

strands in the developing cell wall – also interferes with cytoplasmic RNA

synthesis – alters the permeability of the cytoplasmic

membrane

112


•  Gram-negative bacteria •  VRE

– VanA – VanB – VanC

•  VISA/VRSA

113


•  Staphylococci •  Streptococci •  Enterococci

•  Bacillus •  Corynebacterium •  Clostridium •  Listeria

114

Vancomycin

•  Used clinically for over 45 years •  Active against gram positive pathogens

– MRSA, MRSE – drug of first choice •  Increasing resistant organisms observed

during 1990’s – e.g. VRE •  Very few cases of VISA and VRSA •  Other Glycopeptides-but they are not

commonly used at this time (e.g. televancin)

115

Vancomycin •  Most common clinical uses

–  Exclusively for gram positive infections –  Drug of first choice for MRSA, MRSE regardless of infection site

BUT not drug of choice for MSSA. Nafcilin or oxacillin is a better choice for MSSA (hint: check allergies: can’t give nafcillin or oxacillin in a patient with a true penicillin allergy)

–  Often added empirically in cases of suspected bacterial meningitis along with 3rd generation cephalosporins

–  Bone and joint infections •  Infected prosthesis infections for methicillin-resistant

pathogens –  Surgery prophylaxis if PCN allergic patient –  PO: Clostridium difficile-after metronidazole tried first (i.e. 2nd line)

116

Appropriate Use of Vancomycin

•  Beta-lactam resistant bacteria

•  Serious allergy to beta-lactams

•  CDAD which fails metronidazole or is severe and life-threatening

•  Prophylaxis for endocarditis following certain procedures

•  Prophylaxis for major surgical procedures involving implantation of prosthetic material or devices with a high rate of MRSA or MRSE infections

117

Vancomycin •  Displays time-dependent pharmacodynamic/

bactericidal activity •  Few published, prospective trials associating

vancomycin serum levels and clinical response

•  Dosing should be individualized (often dosed by pharmacy)

•  Established peak and trough ranges based primarily on clinical observations

•  Trough levels most commonly used to monitor therapy for safety and efficacy at this time.

118

Inappropriate Uses •  Routine surgical

prophylaxis •  Single positive BC for

coag(-) staph –  likely a contaminant

•  Continued empiric therapy with negative cultures for MRSA/MRSE

•  First-line tx of CDAD •  Prophylaxis for infection or

colonization of catheters •  Eradication of MRSA

colonization •  Selective decontamination

of the GI tract •  Routine prophylaxis of very

LBW infants •  Routine prophylaxis in HD

or CAPD

119

Pharmacokinetics •  Insignificant

absorption following oral administration (used only for C.Diff)

•  Penetrates well into most body tissues

•  Crosses BBB ONLY when meninges inflamed

•  Half-life = 6-10 hrs

•  Levels –  peak: 20-40 mg/L –  trough: 10-15 mg/L

•  Relatively large Vd –  0.6-0.9 L/kg

•  Eliminated via glomerular filtration

120

Adverse Effects

•  Red Neck (Man) Syndrome •  Thrombophlebitis •  Ototoxicity •  Nephrotoxicity •  Other

– hyperbilirubinemia – neutropenia, anemia, thrombocytopenia

121

Aminoglycosides

122

Aminoglycoside Antimicrobials

•  Streptomyces group – Streptomycin – Neomycin (Mycifrandin ®) – Kanamycin (Kantrex®) – Tobramycin (Nebcin®) – Amikacin (Amikin®)

•  Micromonospora group – Gentamicin (Garamycin®) – Netilmicin (Netromycin®)

123

Mechanism of Action

•  Involves inhibition of bacterial protein synthesis – bind irreversibly to 30S ribosomal subunit

•  Disruption of protein synthesis –  rapid cell death-loss of essential cellular

contents •  Irreversible binding of AG

– prolonged postantibiotic effect

124


• Adaptive resistance – If 1st exposure is sub-lethal,

• organism may decrease its AG uptake – Exposure of the organism to a high

initial AG concentration is important • Concentration-Dependent Killing

125


•  Acquired resistance – Decreased permeability – Reduced binding affinity for ribosomal

target site – Enzymatic inactivation

• Amikacin -least susceptible – contains 3 sites that must be enzymatically

modified vs. 2 sites on other AG

126

Synergy

•  AG require active transport to penetrate into the cell wall of the bacteria

•  Enterococci and streptococci are innately resistant to low levels of AG

•  Cell wall synthesis inhibitors – beta-lactams and vancomycin increase AG

penetration into the bacteria – SYNERGY

127


•  Gram (-) bacilli (major clinical role) •  Activity against Gram (+) cocci is highly

variable •  Gram (-) cocci (Neisseria and Moraxella)

usually susceptible •  No anaerobic coverage •  Synergy: Enterococcus, Streptococci

128

Clinical Uses •  Pseudomonas aeruginosa infections

– Used with extended-spectrum penicillins (piperacillin) for treatment of severe infections

•  With ampicillin –  treatment of severe enterococcal infections

•  With clindamycin or metronidazole –  treatment of severe intra-abdominal infections

129

Clinical Uses

•  Most common clinical uses –  Additive therapy in combination with carbapenems or β-lactams for enhanced gram-negative activity

–  UTIs, pyelonephritis, prostatitis –  Endocarditis – synergy –  Nosocomial pneumonia –  CF –  Any Pseudomonas aeruginosa infection in

combination with other antipseudomonals –  In combination against selected resistant pathogens –  Be leary of combining with vancomycin: very

nephrotoxic 130

Pharmacokinetics •  Oral bioavailability is

negligible •  Administered parenterally •  PO neomycin rarely used any

more •  Half-life 2 hrs in normal

individuals •  Low protein binding •  Vd ~ = to extracellular space •  Penetrate BBB poorly and do

not attain high levels in the lungs

•  95% eliminated renally

•  Obtain peaks and troughs after reaching SS (usually after 5th dose)

•  Extended Interval dosing –  Concentration –dependent

killing –  Post antibiotic effect –  Potentiates tissue penetration –  Reduces ADRs –  Give higher dose and less

frequent intervals (q24,36, 48hr)

•  Use a graph to calculate frequency

•  Can’t be used in everyone

131

Adverse Effects •  Nephrotoxicity

–  AG bind to brush border cells of renal tubules (saturable process).

•  accumulation -release of toxic hydrolases, killing the cells, which slough off into the lumen resulting in decreased GFR.

–  Always reversible –  5-10% frequency –  Use caution when giving with other nephrotoxins (e.g.

amphotericin B, cyclosporine, vancomycin)

132

Adverse Effects

•  Ototoxicity – Accumulation of AG in inner ear tissues

•  destruction of sensory hair cells in the cochlea and vestibular labyrinth

– Manifested as auditory toxicity, vestibular toxicity, or both

– May be preceded by tinnitus or sensation of fullness

– Reversible if caught early but rare – Vestibular toxicity is usually irreversible

133

The Macrolides

134

Macrolide/Azolid Agents

•  Erythromycin (E-Mycin®, Ery-Tab®,Erythrocin®) – Base – Estolate – Ethylsuccinate – Stearate – Lactobionate

•  Clarithromycin (Biaxin®, Biaxin -XL ®,)

•  Azithromycin (Zithromax®)

•  Dirithromycin (Dynabac®)

135

Mechanism of Action

•  Reversibly binds to the 50s subunit of bacterial ribosomes –  Results in inhibition of bacterial protein synthesis.

•  Macrolides are generally considered bacteriostatic –  may be bacteriocidal when present in high

concentrations –  when used against highly susceptible organisms

136

Mechanisms of Resistance •  Decreased penetration

– Gram (-) bacteria •  Altered target site (most common) •  Inactivation by bacterial esterases •  Active efflux from the bacterial cell

137

Macrolides do not cover:

•  MRSE or MRSA •  Enterococci •  Enterobacteriaceae •  Pseudomonaceae •  Neisseria meningitidis (does not penetrate

BBB) •  Bacteroides fragilis

138

Macrolide coverage includes...

ERY Clar AZR MSSA/MSSE ± + + Streptococcus + + + N. Gonorrhoeae + + + M.catarrhalis + ++ ++ H. Influenzae ± + + H. Ducreyi + + + Legionella + + +

139

Macrolide coverage includes...

ERY Clar AZR Mycoplasma + + + Chlamydia + + ++ MAC + + H. Pylori +

140

Pharmacokinetics •  Bioavailability

–  Oral erythromycin varies with formulation •  Bioavailability of base reduced by food •  Stearate preparations -acid unstable, estolate are

more acid stable •  Ethylsuccinate preparations -absorbed unchanged •  Enteric-coated may have greatest oral bioavailability •  Lactobionate are parenteral preparations

–  Clarithromycin ~ 55%. •  Administer with food- increases extent of absorption

–  Azithromycin ~37%. •  Administered 1 hr b/f or 2 hr after meals

141

Pharmacokinetics cont…. •  Distribution- extensive except BBB •  Erythromycin metabolized-

–  several inactive metabolites in liver –  ~2-5% eliminated unchanged in urine –  Clarithromycin ~30-40% excreted unchanged in urine ~10-50% as a

metabolite, rest eliminated via the biliary route

–  Azithromycin is not hepatically metabolized •  Half-life of Ery ~1.5-2h, Clarithromycin 4-5hr,

Azithromycin ~ 50-70h •  Due to low bioavailability recommended to

load azithromycin –  i.e. Zpak dosing: 500mg day 1: 250mg days 2-5 142

Macrolides: Toxicity

Common Gastrointestinal (erythromycin): Nausea/vomiting/diarrhea (30%) -Erythromycin motilin receptor agonist in GI tract

Uncommon Gastrointestinal (azithro, clarithro): Nausea/vomiting/diarrhea (1-5%) Hepatic: transaminase elevation (1-5%) -usually transient, resolves upon d/c

Rare Sensory: ototoxicity (<1%) -Hearing loss, usually reversible Hepatic: severe hepatotoxicity, cholestatic jaundice (<1%) Cardiac: QT prolongation, arrhythmias (<1%) -Indirect: drug interaction effects on proarrythmics -Direct: HERG channel blockade, torsades des pointes

143

Macrolides: Drug Interactions

Second Drug Action Rifampin, rifabutin ↓  Macrolide levels à failure

↑ Rifabutin levels à uveitis Phenytoin ↑ 2nd Drug levels à sedation

Amiodarone, quinidine, sotalol ↑ 2nd Drug levels à arrhythmia

Tacrolimus Cyclosporine

↑ 2nd Drug levels à nephrotoxicity

Benzodiazepines Statins Ca-channel blockers Warfarin

↑ 2nd Drug levels à various dose-related adverse effects

Interaction Profile 1A2 2C9 2C19 3A4 Erythro > clarithro >>> azithromycin

Inhibitor + Inhibitor + Inhibitor + Inhibitor ++ Substrate +

144

Telithromycin (Ketek®)

145

•  A ketolide, oral only •  Related to macrolides •  MOA-blocks protein

synthesis by binding at 23RNA of 50S ribosomal unit

•  Resistance-production K-peptide and riboprotein (target site)mutations

•  For gram + infections •  Has activity against

macrolide resistant pneumococci

•  Oral only •  SE-GI, headache,

hypersensitivity •  QT interval

prolongation •  Contraindicated in

patients with myasthenia gravis

146

Metronidazole (Flagyl®)

147

Mechanism of Action •  Nitroimidazole containing a nitro group which is

reduced within the cells of susceptible organisms –  yielding highly toxic intermediates which damage

microbial DNA of organism •  Most effective in active obligate anaerobes •  Bactericidal

148


•  Aerobes- innately resistant due to its MOA • reduction reaction needed to produce

toxic metabolites that damage microbial DNA competes with oxygen for available electrons

•  Rare acquired resistance

149


•  All obligate anaerobes –  Bacteroides fragilis –  Clostridium difficile (AOC for CDAD)

•  Gardnerella vaginalis •  Trichomonas vaginalis •  Invasive amebiasis •  Giardia intestinalis

150

Pharmacokinetics •  Oral absorption 100% (bioavailability) •  Similar peak concentrations are attained after

oral and IV doses •  Crosses CNS •  Half life is 8 hrs. Now recommended to use q12h

dosing instead of q 8 or q 6 h. •  Hepatically metabolized. 60-80% is eliminated in

urine as parent and metabolites •  May need to decrease dose by 50% in severe

hepatic impairment

151

Adverse Effects •  Gastrointestinal

–  most common (n/v/d) •  Disulfiram like reaction

(flushing, HA, sweating, abdominal pain, N/V)

•  Do not take with alcohol –  Altered taste sensation

(metallic taste) •  Neurologic

–  HA, dizziness, or confusion. High doses cause seizures, ataxia, paresthesias

–  Peripheral neuropathy (<1%)

•  Other –  Discoloration of urine to a

dark reddish brown. –  Do not use in 1st trimester or

during breast feeding •  Drug Interactions -Warfarin: increased INR,

risk of bleeding -Alcohol: potential for

disulfiram-like reaction

152

The Fluoroquinolones

153

Fluoroquinolones

•  First-Generation – Nalidixic Acid - obsolete

•  Second-Generation – Add pseudomonas coverage – Urine - Norfloxacin – Systemic- Ciprofloxacin, Ofloxacin

154

Fluoroquinolones

•  Third-Generation – Add Strep. pneumoniae – Levofloxacin – Sparfloxacin

•  Fourth Generation – Add anaerobes – Moxifloxacin (Avelox)

155

Mechanism of Action

•  Inhibit DNA gyrase, – enzyme that catalyzes the formation of

supercoiled bacterial DNA – stabilize enzyme in tertiary complex after the

insertion of a single strand break – cell is unable to repair break - death results

•  Bactericidal •  Active against-dividing and stationary

bacterial cells

156


• Reduced binding affinity for DNA gyrase

• Decreased cell wall permeability due to changes in porion channels

157

Spectrum of activity

•  Spectrum: –  G(-): Enterobacteriaceae, enteric pathogens –  G(+): MSSA, some Strep –  Atypicals: Legionella, Mycoplasma, Chlamydia

•  First-Generation –  UTIs (seldom used)

•  Anti-pseudomonal: ciprofloxacin, levofloxacin •  Respiratory organisms: moxifloxacin, levofloxacin

–  H. influenzae, Moraxella, Neisseria and atypicals like Chlamydia trachomatis, mycobacterium tuberculosis

•  Anaerobes: moxifloxacin •  B. fragilis

158

Pharmacokinetics •  Oral Bioavailability of

80-100% •  Easily convert from IV

to PO dosage form •  Wide extravascular

distribution and tissue penetration –  Negligible protein

binding –  Small molecular size –  modest CSF penetration

•  Eliminated renally •  Dosage adjustment in

patients with mild-to-moderate renal impairment (CrCl < 50 ml/min) (levofloxacin, ciprofloxacin) not necessary with moxifloxacin

159

Adverse Effects •  QT prolongation •  Gastrointestinal •  Neurologic

–  dizziness, headache, restlessness, tremors

–  dose related and more common in elderly

–  GABA inhibition •  C.diff •  Hypersensitivity

–  mild-to-moderate rash

•  Hyper/hypoglycemia •  Musculoskeletal

–  cartilage erosion and arthropathy in weight bearing joints of animals

–  contraindicated in pregnancy and nursing mothers

–  use in children < 18 should be limited

•  Drug Interactions •  -Oral divalent/trivalent

cations (Ca, Mg, Fe, Al): reduced concentration of orally administered fluoroquinolones via chelation

160

The Tetracyclines

161

Tetracycline Classes

•  Short-acting – Tetracycline (Achromycin®, Sumycin®) – Oxytetracycline (Terramycin®)

•  Intermediate-acting – Demeclocycline (Declomycin®)

•  Long-acting – Doxycycline (Vibramycin®) – Minocycline (Minocin®)

162

Mechanism of Action

•  Bind to the 30S subunit of the 70S bacterial ribosome –  prevents production of essential bacterial proteins

•  Bacteriostatic-reversible binding •  Concurrent administration with B-lactams - mask

bactericidal actions of B-lactams

163


• Prevention of accumulation within the cell – decreased influx – increased ability of cell to actively

remove antibiotic (increased efflux)

164

Spectrum of Activity •  Vibrio species •  UTIs associated with

E. coli or P. mirabilis •  Acute exacerbations

of chronic bronchitis •  H. pylori •  Outpatient therapy for

CAP

•  Propionibacterium acnes

•  Borrelia burgdorferi (Lyme disease)

•  Chlamydia •  Mycoplasma

pneumoniae •  Rickettsia (Rocky

Mountain Spotted Fever)

165

Pharmacokinetics •  Irregular absorption

–  Take on empty stomach except for doxycycline and minocycline

•  Chelate polyvalent metal ions –  Ca, Mg, Iron, Al –  Separate dosing from

MVI, Ca, Iron •  Widely distributed

–  placenta, breast milk

•  Hepatic metabolism; eliminated in urine/feces

•  Should not admin to renally impaired pts due to antianabolic effect –  inhibits protein synthesis

which results in metabolism of AA and azotemia

–  occurs with all tetracyclines except doxycycline

166

Adverse Effects •  Gastrointestinal

–  anorexia, nausea, vomiting

–  dose-related •  Musculoskeletal

–  discoloration of teeth, retardation of skeletal growth

–  contraindicated in pregnant women and kids up to age 8

•  Phototoxicity •  Hepatotoxicity

–  dose-related with IV (>2 g/day)

–  fat deposition in liver •  Neurologic (Minocin)

–  dizziness, loss of balance, tinnitus

•  Oral/vaginal Candida superinfections

167

Trimethoprim-Sulfamethoxazole (TMP/

SMX,Bactrim®)

168

Mechanism of Action

•  SMX- inhibits conversion of Para-aminobenzoic acid (PABA) to dihydropteroic acid

•  TMP- inhibits bacterial dihydrofolate reductase •  Overall effect: inhibition of biosynthesis of

tetrahydrofolic acid, a precursor in the synthesis of certain nucleosides and amino acids

•  Classified as an antifolate

169


• Decreased cell permeability • Overproduction of dihydrofolate

reductase or PABA • Reduced binding affinity of

enzymes

170


•  Staph and Strep •  Neisseria •  H. influenzae •  Moraxella catarrhalis •  Enterobacteriaceae •  Pseudomonas

cepacia •  Stenotrophomonas

maltophilia

•  Brucella •  Chlamydia •  Pneumocystis carinii •  Enterococcus,

Salmonella, Shigella, Pseudomonas aeruginosa, and obligate anaerobes are RESISTANT

171

Antifolates: ADME

Absorption • PO well-absorbed (~90%); also available as IV

Distribution • Wide distribution, good CNS penetration

Metabolism • Some metabolism Adjust in hepatic dz? • No Excretion • Mostly eliminated in urine Adjust in renal dz? • Yes

Drug Interactions -Warfarin: increased INR, risk for bleeding

Adverse Effects

•  Cutaneous –  mild skin rashes –  SJS and TEN are rare

•  Hematologic –  thrombocytopenia –  neutropenia (AIDS pts) –  hemolytic anemia –  megaloblastic anemia

•  Neurologic –  headache, depression,

hallucinations, tremor •  Hepatotoxicity •  Reversible

hyperkalemia •  Benign, reversible

elevation of SCr

173

Miscellaneous

•  Linezolid (Zyvox) •  Daptomycin (Cubicin) •  Quinupristin/dalfopristin (Synercid®) •  Alternatives to vancomycin for resistant

gram positive infections •  Very expensive and need to be reserved

for resistant infections

174

Linezolid (Zyvox) Mechanism of Action

•  Oxazolidinone •  Inhibits bacterial protein synthesis by

binding to site on 23S ribosomal RNA of the 50 S subunit and prevents formation of functional 70S initiation complex (essential component for translation process)

•  Bacteriostatic against enterococci and staphylococci

•  Bacteriocidal for streptococci

175

Mechanism of Resistance

•  Mutations in 23S RNA

176


•  Enterococcus faecium (vancomycin resistant strains)

•  Staphylococcus aureus (including methicillin-resistant strains)

•  Strep agalactiae, pneumoniae (including multi-drug resistant isolates), pyogenes

177

Oxazolidinones: ADME

Absorption • PO form has 100% absorption (bioavailability)

Distribution • Wide distribution, including CNS but not to be used in bacteremia (concentrations are maintained high enough)

Metabolism • Nonenzymatic oxidation; mild-moderate inhibitor of monoamine oxidase

Adjust in hepatic dz? • No Excretion • Metabolites excreted in urine Adjust in renal dz? • No

Drug Interactions -Serotenergic drugs (SSRIs, TCAs, triptans): risk of serotonin syndrome with co-administration (often prevents use)

Adverse Effects

•  Myelosuppression- monitor CBC weekly •  Diarrhea, Headache, Nausea

179

Oxazolidinones: Toxicity

Uncommon Hematologic: Thrombocytopenia, neutropenia, anemia (1-5%) -Mild-moderate myelosuppression -Seen w/tx courses >7-10 days -Reversible on d/c Gastrointestinal: Nausea/vomiting/diarrhea (1-5%)

Rare Metabolic: Mitochondrial toxicities (<1%) -Peripheral neuropathy, optic neuritis -Lactic acidosis -Associated with prolonged (>4 weeks) duration of treatment -May be irreversible

180

A point to consider

•  Linezolid is VERY expensive as an OP Rx (~$55/tablet)

•  Given BID for 7-10 days •  Clinical judgment MUST be used before

prescribing this in an OP setting •  There are assistance programs now

available: work closely with case management to utilize these programs

181

Daptomycin (Cubicin®) •  Classified as a lipopeptide •  Indications •  Complicated skin and skin structure

infections –  caused by susceptible isolates of the following Gram-

positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only).

–  Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.

182

Daptomycin (Cubicin®) •  Not indicated for the treatment of pneumonia •  Patients need to monitor for development of muscle

pain/ weakness particularly of the distal extremities. •  Monitor CPK levels weekly- any unexplained elevations

should be monitored more frequently. •  Discontinue in patients with unexplained signs and

symptoms of myopathy in conjunction with CPK elevation >1000 U/L, or in patients without reported symptoms who have marked elevations in CPK (≥10X ULN).

•  Most adverse events -mild to moderate in intensity. The most common were anemia, constipation, diarrhea, nausea, vomiting, injection site reactions, and headache.

183

Lipopeptides: ADME Absorption • IV only

Distribution • High protein binding; unknown/questionable CNS penetration; inactivated by pulmonary surfactant (not useful for pneumonia)

Metabolism • Minimal hepatic metabolism Adjust in hepatic dz? • No Excretion • >60% eliminated in urine Adjust in renal dz? • Yes

Lipopeptides: Resistance: Uncommon, mechanisms poorly defined

Lipopeptides: Toxicity

Uncommon Musculoskeletal: Myopathy (1-5%) -Muscle pain/weakness in skeletal muscle -With/without elevation in creatine phosphokinase (CPK) -Reversible on drug discontinuation -Monitor symptoms of myalgias; consider monitoring CPK

Rare Musculoskeletal: Rhabdomyolysis (<1%) -Muscle breakdown with renal damage -Associated with elevations in CPK -D/c dapto if CPK>10x ULN w/ or w/o sxs

185

Quinupristin/dalfopristin (Synercid®)

•  Streptogramin •  Serious or life-threatening infections associated

with vancomycin-resistant Enterococcus faecium (VREF) bacteremia.

•  Also approved for complicated skin and skin structure infections caused by Staphylococcus aureus (methicillin susceptible) or Streptococcus pyogenes

•  Standardized dosing regardless of renal impairment: 7.5 mg/kg IV q8h for vancomycin-resistant E faecium and 7.5 mg/kg IV q12h for complicated skin and skin structure infections

186

Quinupristin/dalfopristin (Synercid®) •  Pharmacokinetic data in patients with hepatic

cirrhosis (Child-Pugh A or B) - dosage reduction may be necessary, but exact recommendations cannot be made at this time

•  common adverse drug reactions - inflammation at the infusion site and pain at the infusion site; arthralgia and myalgia and nausea

•  P450 3A4 substrates (e.g., cyclosporin A, midazolam, nifedipine, and terfenadine) should be used with caution and monitored when coadministered Those drugs used concomitantly that may prolong the QTc interval should be avoided.

187

Tigecycline (Tygacil®) •  Newer Class – Glycylcycline (structurally similar

to tetracylines); IV only •  Inhibits protein translation in bacteria by binding

to the 30S ribosomal subunit •  Very broad spectrum, aerobes, anaerobes, gram

negative, and gram positive including MRSA, MRSE, and VRE –  For skin/skin structure infections and intra-abdominal

infections •  May cause permanent tooth discoloration in

pediatrics-avoid in pregnancy and those under 8 years

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Tigecycline (Tygacil®) •  Dosage reductions in patients with Childs Pugh C •  Monitor PT/INR if used with warfarin •  May decrease effectiveness of oral contraceptives •  March 2011 FDA caution on increased mortality in

pneumonia patients •  Adverse effects similar to tetracylines:

–  photosensitivity, pseudotumor cerebri, pancreatitis, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hypophosphatemia

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Clostridium difficile Risk by Antimicrobial Therapy

Characteristic Adjusted hazard ratio (95% Confidence Interval)

Penicillins 1.9 (0.9 – 4.0) B-lactamase combos 2.3 (1.5 – 3.5) 1st – 2nd Gen Cephs 2.4 (1.4-4.1) 3rd- 4th Gen Cephs 3.1 (1.9 – 5.2) Glycopeptides 2.6 (1.7 – 4.0) Clindamycin 1.9 (0.8 – 4.4) Macrolides 1.5 (0.7 – 3.1) Aminoglycosides 0.9 (0.3 – 3.0) TMP/SMX 1.9 (1.1 – 3.4) Fluoroquinolones 4.0 (2.7 – 5.9) Metronidazole 0.3 (0.1 – 0.9)

Stevens V, et al Clin Infect Dis 2011;53:42-48 190

Some Information Sources

•  Sanford Guide-updated yearly •  Infectious Disease Society of America

– http://www.idsociety.org/

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