Review of Antibiotics Part 1

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Review of AntibioticsPart 1

• Gary R. Skankey, MD, FACP, FIDSA
• University of Nevada
• School of Medicine

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Penicillin - Spectrum

• Lancfield group streptococci
• Alpha streptococcus, except pneumococcus
• Enterococcus
• Oral anaerobes - peptostreptococcus, etc.
• Treponema pallidum and other spirochetes
• Actinomyces

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Penicillin - Mechanism of Action

• Penicillin is a beta-lactam antibiotic
• Binds to penicillin binding proteins on bacterial
  cell surface
• Inhibits cell wall synthesis

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Penicillin and Pneumococcus

• About 30 resistant, 15 intermediately sensitive
• Altered PBPs makes penicillin and sometimes
  cephalosporins ineffective
• Plasmid mediated,possibly transferred from other
  species
• Plasmid also caries resistance genes to other
  antibiotics macrolides, tetracyclines, sulfa
  drugs

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Penicillin - Neisseria

• Increasing resistance due to beta-lactamase
  production in N. gonnorrhea and N. meningitidis
• Unless organism proven sensitive, do not use
  penicillin empirically for meningitis or sexually
  transmitted disease.

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Penicillin - Dosing

• Mild infections - cellulitis, pharyngitis, etc.,
• Penicillin V 500mg PO QID
• Penicillin G 1 - 2 million units IV Q4hrs
• Serious infections - meningitis, endocarditis
• Penicillin G 4 million units IV Q4hrs.
• Syphillis
• latent 2.4 million units benzathine penicillin
  IM Q week x 3 weeks
• neurosyphillis 4 million units IV Q4hrs x 10
  days
• Adjust dose for renal failure

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Penicillin - Clinical Uses

• Syphillis
• S. pyogenes pharyngitis
• Actinomyces infections
• Subacute bacterial endocarditis due to
  pcn-sensitive alpha-streptococci
• Pencillin-sensitive pneumococcal and
  meningococcal meningitis

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Ampicillin - Spectrum

• Same gram positives as penicillin
• Enteric gram negatives (if sensitive)
• E. coli
• Proteus
• Salmonella
• Shigella
• Respiratory tract gram negatives
• Haemophillus influenzae, Moraxella morganii
• Pasteurella moltocida
• Listeria monocytogenes

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Ampicillin and Enteroccocus

• Weak affinity for penicillin-binding proteins
  bacterostatic
• Must add aminoglycoside (gentamicin) to create
  bacterocidal regimen
• E. faecalis usually sensitive
• E. faecium usually resistant

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Ampicillin and Haemophillus

• About 40 of H. influenzae is resistant
• Produces beta-lactamase
• Resistance overcome by use of beta-lactamase
  inhibitor

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Ampicillin and Salmonella

• Increasing resistance in salmonella makes it
  unreliable against typhoid fever.
• About 40 resistance

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Ampicillin - Dosing

• Mild infections - cystitis, pharyngitis
• Amoxacillin 500 mg PO TID
• Moderate infections - pyelonephritis, cellulitis,
  osteomyelitis
• Ampicillin 1 - 2 gm IV Q6hrs
• Severe infections - meningitis, endocarditis
• Ampicillin 2 gm IV Q4hrs
• Adjust dose for renal failure

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Ampicillin - Clinical Uses

• Amoxacillin for ampicillin-sensitive UTIs
• In combo with gentamicin for enterococcal
  endocarditis
• Listeria monocytogenes infections
• meningitis
• bacteremia
• Cat bite cellulitis clindamycin
• Penicillin-sensitive alpha-streptococcal SBE

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S. aureus - beta lactamase

• 1st described in 1945
• Confers resistance to penicillin and ampicillin
• Coded for on plasmid
• Plasmids also carry resistance to other
  antibiotics
• Usually inducible

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Beta-lactamase-Resistant Penicillins

• Methicillin
• high risk of interstitial nephritis, no longer on
  market
• Nafcillin
• Oxacillin
• Dicloxacillin (PO)

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Nafcillin/Oxacillin - Spectrum

• Oxacillin-sensitive S. aureas
• Oxacillin-sensitive coagulase negative staph
• Okay against Lancfield group streptococci and
  viridans streptococci, but there are better drugs
  for these
• No gram negative or anaerobic coverage to speak of

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Nafcillin/Oxacillin - Pearls

• Most potent anti-staph drug made
• Excellent CNS penetration (staph meningitis)
• No dose adjustment for renal failure
• predominantly hepatic excretion
• Watch out for
• leukopenia
• thrombocytopenia
• interstitial nephritis

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Nafcillin/Oxacillin - Clinical Uses

• All MSSA infections
• Endocarditis
• Meningitis
• Osteomyelitis
• Pneumonia
• Abscesses
• Cellulitis

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Anti-pseudomonal Penicillins

• Carbenicillin
• no longer on the market
• Ticarcillin
• only on market as Timentin
• Piperacillin
• hard to get as piperacillin alone, usually only
  available as Zosyn

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Piperacillin - Spectrum

• Pseudomonas
• Enterobacteriacae group
• Beta-lactamase negative Moraxella, Neisseria,
  Haemophillus
• Same gram positive spectrum as penicillin
• Same anaerobic spectrum as penicillin

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Piperacillin dosing

• Mild to moderate gram negative (non-pseudomonal)
  or streptococcal infections
• 3 gm IV Q6 hrs.
• Moderate to severe pseudomonal infections
• 3 gm IV Q4 hrs.
• Or Piperacillin/tazobactam 3.375 gm IV Q4 hrs

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Beta-lactam/Beta-lactamase Inhibitor Combinations

• Unasyn
• ampicillin/sulbactam
• Timentin
• ticarcillin/clavulenate
• Zosyn
• piperacillin/tazobactam

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Unasyn - Spectrum

• Streptococci
• MSSA
• All anaerobes
• Beta-lactamase-producing gram negatives
• Enterococcus - bacterostatic
• Penicillin-sensitive pneumococcus

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Unasyn - Dosing

• Mild infections
• 1.5 gm IV Q6 hrs.
• Moderate to severe infections
• 3.0 gm IV Q6 hrs.
• Adjust dose for renal failure

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Unasyn - Clinical Uses

• Head and neck infections
• Peritonsilar abscess
• Sinusitis
• Mastoiditis
• Mandibular osteomyelitis
• Actinomyocosis
• Infected Bite Wounds
• Human
• Dog
• Cat
• Diabetic Foot infections, including osteomyelitis
• Culture negative endocarditis

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Zosyn - Spectrum

• Streptococci
• MSSA
• All anaerobes
• Beta-lactamase-producing gram negatives
• Enterococcus - bacterostatic
• Piperacillin-sensitive pseudomonas
• 18 gm per 24 hrs

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Zosyn - Dosing

• Usual dosing
• 3.375 gm IV Q6 hrs.
• Fulminant sepsis
• 4.5 gm IV Q6 hrs.
• Pseudomonas sepsis
• 3.375 gm IV Q4 hrs
• Adjust dose for renal failure

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Zosyn - Clinical Uses

• Intra-abdominal infections
• Nosocomial aspiration pneumonia
• Diabetic foot infections when Pseudomonas might
  be involved
• Pulmonary infections in patients with
  bronchiectasis or cystic fibrosis

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Cephalosporins

• Inhibit cell wall synthesis - peptidoglycan
• Side effects are mild
• rash
• eosinophilia
• leukopenia
• leukocytosis
• biliary sludge (ceftriaxone)
• thromobocytosis

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First Generation Cephalosporins

• Cefazolin - Ancef IV
• Cephalothin - Keflin IV
• Cephalexin - Keflex PO
• Cephradine - Velosef PO
• Cefadroxil - Duricef PO

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Ancef - Spectrum

• Staphylococcus
• Streptococcus
• E. coli, Proteus, Klebsiella if sensitive

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Ancef - Clinical Uses

• Any MSSA infection
• Cellulitis (2 gm IV Q8 hrs.)
• Osteomyelitis
• Endocarditis
• Pneumonia
• Not for meningitis
• Any Lancfield or viridans group streptococcal
  infections
• Endocarditis
• Cellulitis
• Sensitive enteric gram negative infections
• UTI

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Second Generation Cephalosporins

• Cefuroxime IV - Zinacef
• Cefotetan IV - Cefotan
• Cefoxitin IV - Mefoxin
• Cefuroxime axitil PO - Ceftin
• Cefaclor PO - Ceclor
• Cefprozil PO - Cefzil

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Cefuroxime/Cefotetan - Spectrum

• H. influenzae
• Anaerobes
• Staphylococcus
• Streptococcus
• Enterobacteriaceae

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1st vs 2nd Generation

• 1ST GENERATION
• H. influenzae -
• S. aureus
• Streptococcus
• Moraxella -
• Gram negatives
• Anaerobes -

• 2ND GENERATION
• H. influenzae
• S. aureus
• Streptococcus
• Moraxella
• Gram negatives
• Anaerobes

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Cefuroxime - Clinical Uses

• Upper respiratory tract infections
• sinusitis
• peritonsilar abscess
• otitis media
• etc.,
• Lower respiratory tract infections
• pneumonia
• acute bacterial bronchitis
• Urinary tract infection

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Cefotetan/Cefoxitin - Clinical Uses

• Intra-abdominal infections
• diverticulitis
• intra-abdominal abscess
• peritonitis
• cholycystitis
• etc.,
• Osteomyelitis
• Diabetic foot infections

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Third Generation Cephalosporins

• Cefotaxime IV - Claforan
• Ceftriaxone IV - Rocephin
• Ceftazidime IV - Fortaz
• Cefixime PO - Suprax
• Cefpodoxime PO - Vantin

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Claforan/Rocephin - Spectrum

• Streptococci
• Viridans, Lancfield groups, pneumococcus
• S. aureus
• Enteric gram negatives
• H. influenzae
• Neisseria meningitidis and gonnorrhea
• some anaerobes

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Fortaz - Spectrum

• All gram negatives, including Pseudomonas
• Weak if any gram positive coverage
• No anaerobic coverage

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Claforan/Rocephin -Clinical Uses

• Meningitis - 2gm Q4 hrs/2gm Q12 hrs
• Community-acquired pneumonia
• UTI
• Upper Respiratory Tract Infections
• sinusitis
• peritonsilar abscess
• Intra-abdominal infections

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Fortaz - Clinical Uses

• Hospital-acquired pneumonia
• Hospital-acquired UTI
• Post-op meningitis
• Intra-abdominal infections
• Pulmonary infections in patients with cystic
  fibrosis or bronchiectasis
• Nail-puncture cellulitis/osteomyelitis

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Fourth Generation Cephalosporin

• Cefepime IV - Maxipime

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ZWITTERIONIC CHEMICAL STRUCTURE
OCH3
N
H N
H
H
S
N
CI-

O
H2O
N
N
S
O
HCI H2N
CH3
COOH
cefepime
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CEFEPIME GASTROINTESTINAL PENETRATION

• Cefepime pharmacokinetics and effects on fecal
  flora were assessed in 8 healthy volunteers who
  received 1 g q12h IV for 8 days
• Elimination was almost entirely renal, with no
  evidence of accumulation
• Minimal changes in intestinal flora (16 genera
  analyzed)

Bächer K et al. J Antimicrob Chemother.
199230365-375.
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GRAM-NEGATIVE IN VITROACTIVITY OF CEFEPIME

• Acinetobacter calcoaceticus subsp lwoffi
• Citrobacter diversus
• Citrobacter freundii
• Enterobacter spp
• Enterobacter agglomerans
• Escherichia coli
• Haemophilus influenzae
• Hafnia alvei
• Klebsiella oxytoca

• Klebsiella pneumoniae
• Moraxella catarrhalis
• Morganella morganii
• Proteus mirabilis
• Proteus vulgaris
• Providencia rettgeri
• Providencia stuartii
• Pseudomonas aeruginosa
• Serratia marcescens

In vitro activity does not necessarily correlate
with clinical results. Cefepime has been shown
to be active against susceptible strains of these
pathogens in clinical infections. Including
?-lactamaseproducing strains.
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GRAM-POSITIVE IN VITROACTIVITY OF CEFEPIME

• Staphylococcus aureus (methicillin-susceptible
  only)
• Staphylococcus epidermidis (methicillin-susceptibl
  e only)
• Staphylococcus saprophyticus
• Streptococcus agalactiae (Lancefield group B
  streptococci)
• Streptococcus pneumoniae
• Streptococcus pyogenes (Lancefield group A
  streptococci)
• Viridans group streptococci

In vitro activity does not necessarily correlate
with clinical results. Cefepime has been shown
to be active against susceptible strains of these
pathogens in clinical infections.
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Maxipime - Clinical Uses

• Hospital-acquired pneumonia
• Sepsis in prolonged hospitalization
• Intra-abdominal infections

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Cephalosporins
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Carbipenems

• Imipenem - Primaxin
• Meropenem Merem
• Ertapenem Invanz
• Doripenem - Dorimax
• Inhibit cell wall synthesis

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Primaxin/Merem/Dorimax - Antibacterial
Spectrum

• Covers everything but
• MRSA
• Stenotrophomonas
• B. cepacia
• pcn-resistant enterococcus (only bacterostatic
  vs.pcn.sensitive strains)
• C. difficile
• some pcn-resistant pneumococcus

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Imipenem - Primaxin Toxicity

• Rash - 50 cross-allergenicity with penicillin
• Seizures
• renal failure (high serum levels)
• intracranial pathology (lowers seizure threshold)
• Nausea/vomiting
• Leukocytosis
• Thrombocytopenia

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Merem - Toxicity

• Same as Primaxin, except
• Minimal seizure risk

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Ertapenem spectrum

• All gram positives (except MRSA, and
  vanco-resistant Enterococcus faecium)
• All gram negatives (except pseudomonas)
• All anaerobes

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Vancomycin
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Vancomycin

• Class - glycopeptide
• Inhibits cell wall synthesis, and RNA synthesis
  (double action)
• Binds to d-ananyl-d-alanine portion of cell wall
  precursor

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Vancomycin - Toxicity

• Red mans syndrome
• histamine release during too rapid infusion
• Ototoxicity
• commonly irreversible
• associated with sustained high doses (peaks gt30)
• Nephrotoxicity
• very uncommon now
• ototoxicity and nephrotoxicity amplified in
  presence of aminoglycoside or high-ceiling
  diuretics

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Vancomycin - Dosing

• Generally 1 gm IV Q12hrs
• Peak and trough with third or fourth dose
• Target peak 30 - 40 ug/dl
• Target trough 10 - 15 ug/dl (mild to moderate
  infections)
• Target trough 15 20 ug/dl (more severe
  infections or those with penetration issues)
• If trough high --gt lengthen interval
• If peak high or low --gt adjust dose

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Vancomycin - Dosing
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Vancomycin - Dosing Random Levels

• Use only when patients serum creatinine is
  unstable
• Write order to give dose as soon as random level
  result known
• Vancomycin 1 gm IV Q24 hrs prn random level lt10
  or lt12
• Never order when patient receiving regularly
  dosed Vancomycin

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Trimethoprim/Sulfamethoxazole

• Each component inhibits sequential steps of
  tetrahydrofolic acid synthesis thus act
  synergistically
• High oral bioavailablilty

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Trimethoprim/Sulfamethoxazole

• Toxicity
• 75 adverse reactions involve skin
• urticarial rash most common
• Stevens-Johnson Syndrome, exfoliative dermatitis,
  toxic epidermal necrolysis are rare
• allergic cholestatic hepatitis
• reversible drop in creatinine clearance in
  patients with normal renal function
• irreversable renal failure in patients with renal
  disease

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Uses of Trimethoprim/Sulfamethoxazole

• Useful alone or in combo with Rifampin in mild
  MRSA infections
• UTI, Bronchitis, cellulitis
• Switch to PO TMP/SMX after a course of IV
  vancomycin
• Use in combination with vancomycin and rifampin
  in serious MRSA infections
• Drug of choice for Stenotrophomonas maltophilia
• Drug of choice for Pneumocystis

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Rifampin

• Inhibits DNA-dependent RNA polymerase
• Concentration in lung exceeds serum levels
• PO IV
• Synergy demonstrated with cefazolin vs MSSA and
  with Vancomycin vs MRSA
• Never use as monotherapy, resistance develops
  rapidly

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Rifampin - Toxicity

• Chemical hepatitis
• GI intolerance
• Increase serum creatinine

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Rifampin - Drug-Drug Interactions

• Increases hepatic metabolism of many drugs thus
  reducing their serum levels
• coumadin
• theophyline
• fluconazole, itraconazole, ketoconazole
• digoxin
• cyclosporin
• propranolol
• sulfonylureas
• prednisone
• dilantin

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Synercid - quinupristin
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Synercid - dalfopristin
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Synercid

• Class Streptogramin
• Quinupristin and dalfopristin act synergistically
• Mechanism of action bind to 50s ribosome to
  inhibit protein synthesis

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Synercid - Antibacterial Spectrum

• MSSA - bacterocidal
• MRSA - bacterocidal
• Vancomycin-resistant E. faecium - bacterostatic
• unreliable vs E. faecalis
• Coag. neg. staph
• Corynebacterium jeikeium
• S. agalactiae
• S. pneumoniae (including pcn-resistant strains)
• S. pyogenes

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Synercid - Administration

• IV form only
• 7.5 mg/kg IV Q8hrs
• No adjustment for renal failure

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Synercid - Drug interactions

• Inhibits cytochrome P450 3A4, thus increases
  levels of
• cyclosporin
• Benzodiazepines
• Ca channel blockers
• antihistamines
• Steroids
• Statins

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Synercid - Side effects

• Infusion site pain and inflammation
• Myalgias
• Arthralgias
• Nausea

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Zyvox (linezolid)
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Zyvox - (linezolid)

• Class - oxazolidinone
• Acts on 50S ribosome
• 100 oral bioavailability
• Bacterostatic
• 65 non-renal excretion - no dosing adjustment
  for renal failure
• Dose 600mg IV or PO Q12hrs
• Minimal drug-drug interactions

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Zyvox - Spectrum of Activity

• FDA indication
• Staphylococcus aureus (MSSA and MRSA )
• Enterococcus faecalis (including VRE)
• Enterococcus faecium (including VRE)
• Streptococcus pneumoniae ( pcn.-resistant and
  pcn.-sensitive )
• Streptococcus pyogenes
• Streptococcus agalactiae (gp B strep)
• Coagulase negative staph (including MR-CNS)
• Viridans group strep
• Pasteurella multocida

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Zyvox - Toxicity

• Thrombocytopenia - about 10
• Diarrhea - 8.3
• Headache - 6.5
• Nausea - 6.2
• Vomiting - 3.7
• Insomnia - 2.5
• Constipation - 2.2
• Rash - 2.0

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