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Wednesday, August 10, 2016

Antibiotics for PAs - Part I

Antibiotics for Physician Assistants - Part I
Updated: 08/07/2016
  • Empiric therapy is defined as the initiation of treatment prior to firm diagnosis, and knowing the specific organism causing the infection
    • Started only after cultures have been obtained
    • Targets likely pathogens and must use local antibiogram
  • Broad spectrum means covering both gram positive and gram negative bacteria
  • Pharmacokinetics: what the body does to a drug
    • Absorption: described in terms of bioavailability (F)
      • 100% bioavailable drugs (PO = IV): Linezolid, Fluoroquinolones, Tetracyclines, Azithromycin, Metronidazole, Trimethoprim/Sulfamethoxazole (Bactrim), Rifampin
    • Distribution: affected by protein binding, blood flow, molecular size, lipophilicity, inflammation, and fluid status
    • Metabolism: occurs primarily in the liver via multiple mechanisms
      • Phase I: oxidation/reduction (CYP 450), hydrolysis
      • Phase II: glucuronidation, sulfonation, methylation, acetylation, glutathione
    • Elimination: primarily renal (glomerular filtration and tubular secretion)
      • Most antibiotics require dose adjustment for creatinine clearance (CrCl) <50 mL/min
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Cell Wall Synthesis Inhibitors


Beta Lactams
(Penicillins, Cephalosporins, and Carbapenems)
Penicillins
  • MOA: binds to penicillin binding proteins on surface of cell wall and inhibits cell wall synthesis
  • Variable PO absorption, short half lives (frequent dosing), primarily renally eliminated

Indications
Dose
Pearls
Penicillin G
Streptococcal infections
Syphilis
Staph aureus (susceptible)
IM/IV: 3-4 million units q 4 hours
Continuous infusion over 24 hours if normal renal function
Penicillin G Benzathine
Syphilis
IM: 2.4 million units x 1 (primary, secondary, early latent)
IM: 2.4 million units weekly (late latent, latent of unknown duration)
IM injection
Longer acting
Penicillin V Potassium (VK)
Actinomycosis
Erysipelas
Streptococcal Pharyngitis
PO: 250-500 mg q 6 hours

Anti-staphylococcus or Penicillinase Resistant
Oxacillin (IV), Nafcillin (IV), Dicloxacillin (PO)
Methicillin-susceptible staph aureus (MSSA)
Narrow spectrum gram (+) coverage

Staphylococcal skin/soft tissue infections (mastitis)
2 grams q 4 hours
Continuous infusion over 24 hours if normal renal function
May increase warfarin requirement (drop INR)


Aminopenicillins: gram negative and positive coverage

Indications
Dose
Pearls
Ampicillin
E. coli
Proteus (K. pneumoniae intrinsically resistant)
Listeria
Enterococcus: gram (+) cocci in pairs; faecalis
Streptococcus: gram (+), viridans, pyogenes, pneumoniae, agalactiae
IV: 2 grams q 4-6 hours
PO:
Gram positive and negative coverage (limited)
Ampicillin/Sulbactam
[Unasyn]
Similar to Ampicillin
Better Gram (-) coverage
Acinetobacter
Anaerobes: E. coli

Skin/soft tissue infections, intraabdominal and peritonitis
IV: 3 grams q 4-6 hours

Amoxicillin
Similar to Ampicillin


UTI in pregnancy, AOM
PO: 500-1000 mg q 8-12 hours
Lower bioavailability than IV ampicillin (greater than PO ampicillin)

Gram positive and negative coverage (limited)
Amoxicillin/
Clavulanate [Augmentin]
Similar to Amoxicillin
Better Gram (-) coverage
Anaerobes (not Acinetobacter): E. coli, Salmonella, Shigella, Campylobacter, H. pylori, Klebsiella

AOM, sinusitis, dental infections, bites
PO: 250-500 q 8 hours OR
PO: 875 mg q 12 hours



Antipseudomonal Penicillins

Indications
Dose
Pearls
Piperacillin/
Tazobactam (Zosyn)
MSSA
Empiric or definitive therapy for Pseudomonas aeruginosa
Anaerobes
Enterococcus: gram (+) cocci in pairs; faecalis
Streptococcus: gram (+), viridans, pyogenes, pneumoniae, agalactiae
IV: 3.375-4.5 g q 6-8 hours
Can be given extended infusion (over 4 hours) or continuous infusion

Zosyn and Cefepime are the empiric broad spectrum agents of choice at most institutions

No atypical coverage (Legionella, Mycoplasma, Chlamydia)


Cephalosporins
  • As you increase generation, you generally add greater gram negative coverage, but lose gram positive coverage
  • Cross-reactivity in patients with penicillin allergy: 10%
    • If patient has had true IgE mediated (anaphylaxis) reaction, avoid all B-lactams including Carbapenems (Exception: can give aztreonam)

Indications
Dose
Pearls
First Generation
Cefazolin (Ancef)
Cephalexin (Keflex)
Staphylococcus: aureus, epidermidis, haemolyticus, saprophyticus
Streptococcus: gram (+), viridans, pyogenes, pneumoniae, agalactiae
Aerobic GRN: M. catarrhalis, E. coli, K. pneumoniae

Skin and soft tissue infections, surgical prophylaxis,
ENT: Streptococcal pharyngitis
GU: UTI
Pediatric osteomyelitis
IV: Cefazolin 1-2 g IV q 8 hours
PO: Cephalexin 250-500 mg q 6 hours (good absorption)
No CSF penetration
Second Generation
Cefuroxime (Ceftin PO, Zinacef IV/IM)
Cefoxitin (Mefoxin)
Aerobic GNR: H. flu, M. cat, N. meningitidis
Anaerobes: E. coli

Skin/soft tissue infections
GU: UTI
Pulm: Mild CAP (3rd Gen preferred), acute chronic bronchitis exacerbation
ENT: sinusitis, AOM
Surgical prophylaxis (GI/GU)
Abdominal infections
PO: Cefuroxime axetil 250-500 mg q 12 hours
IV: Cefuroxime 1.5 g q 8 hours
IV: Cefoxitin 1-2 grams q 4-6 hours

Third Generation
Ceftriaxone (Rocephin)
Cefotaxime (Claforan)
Ceftazidime (Fortaz, Tazicef)*
Improved Anaerobic GNR: E. coli, Klebsiella, P. mirabilis, S. pneumoniae
MSSA coverage
*Ceftazidime: Pseudomonas

Ceftriaxone: Meningitis
Gonorrhea, CAP
IV/IM: Ceftriaxone 1-2 g q 24 hours (2 g q 12 for meningitis)
IV: Cefotaxime 1-2 g q 4-8 hours
IV: Ceftazidime 1-2 g q 8 hours
Ceftriaxone - good CNS penetration (higher dose)
Fourth Generation
Cefepime (Maxipime)
Empiric or definitive therapy against Pseudomonas aeruginosa
Febrile neutropenia
IV: 1-2 grams q 8-12 hours
Unlike Zosyn, no anaerobic or enterococcus activity
Less gram positive coverage than lower generations
Fifth Generation
Ceftaroline (Teraflo, Zinforo)
GN coverage similar to ceftriaxone
Streptococcus
Staphylococcus (MRSA)
IV: 600 mg q 8-12 hours



Monobactams
Aztreonam
Gram negative only
Pseudomonas
IV: 2 grams q 6-8 hours
No cross-reactivity with other beta-lactams


Carbapenems
Ertapenem
Gram negative coverage: ESBL producing Enterobacteriaceae
Streptococcus
MSSA
Anaerobes
IV: 1 g q 24 hours

Meropenem
Same as Ertapenem
Pseudomonas aeruginosa
Acinetobacter
Enterococcus
IV: 1 g q 8 hours
IV: 2 g q 8 hours (CNS)
Broad spectrum activity, limit activity
Imipenem/Cilastatin
Primaxin
Similar to Meropenem
Nocardia
Nontuberculous mycobacterial organisms
IV: 500 mg q 6 hours
Imipenem is rapidly inactivated by renal dehydropeptidase I (DHP-1), cilastatin is a DHP-1 inhibitor that allows for a prolonged half life and increased tissue penetration


Adverse Effects of Beta Lactams
  • Hypersensitivity
    • Cross reactivity of cephalosporins is <10%
    • Avoid all beta-lactams for anaphylactic reactions, including carbapenems
      • Exception: can give aztreonam
  • Seizures: higher risk with carbapenems
    • Highest when not renally-dosed
    • Nafcillin, oxacillin, and ceftriaxone - only beta-lactams that do not require renal adjustment
  • Electrolyte Imbalance (Na and K): most often with salts (penicillin G potassium or nafcillin sodium)


Other Bacterial Cell Wall Agents
  • Binds to the D-ala-D-ala terminus of the peptidoglycan molecule preventing cross linking of the chains by penicillin binding protein → weakens cell wall and causes osmotic lysis
Vancomycin
(Vancocin)
Aerobic gram (+): MRSA, MSSA, S. pneumoniae
Anaerobic gram (+)

Empiric therapy when MRSA suspected, MDRS in CA meningitis, severe infections with MRSA, CoNS, Enterococcus resistant to ampicillin

Sepsis, meningitis, pneumonia, infective endocarditis
Loading dose of 25 mg/kg in critically ill patients
Maintenance dose: 15 mg/kg based on TBW
Frequency based on renal function (most q 12)
No gram (-) activity

PO formulation for C. difficile due to poor absorption

Bactericidal, slower than B-lactams
Bacteriostatic against Enterococcus

Trough levels used to determine efficacy and nephrotoxicity (goal: 15-20)
SCr: baseline and every 3-4 days


Bacitracin
(BACiiM, Bacitracin)
Gram (+) and Gram (-) activity
Staphylococcal pneumonia, aureus, epidermidis
Streptococcus pyogenes
IM
Topical
Decreased incidence of cross reaction with sulfa drugs when not combined with polymyxin B and neomycin


Cyclic Lipopeptide
  • Calcium-dependent insertion of lipid tail leading to disruption of cell membrane and cell death
Daptomycin
(Cubicin)
MDRS and gram (+)
MRSA, MSSA, VRE, S. pneumoniae, another streptococcal spp.

Must have failed or had intolerant response to vancomycin
IV (skin/soft tissue): 4 mg/kg daily
All other: 6-8 mg/kg daily, based on TBW
No gram negative activity
Not for use in pneumonia (lung surfactant binds the drug)

Monitor CPK at baseline and weekly


Phospholipid Membrane Inhibitor
  • MOA: Bind to outer membrane of GN bacteria leading to disruption of membrane instability and leakage of cellular contents
Polymyxin
Colistin (colistimethate sodium)
Highly resistant GNR, including Pseudomonas and Klebsiella
Acinetobacter
CRE: Carbapenem resistant Enterobacteriaceae

Multidrug resistant GN infections: pneumonia, bacteremia, sepsis, complicated UTIs
IM, IV
Ophthalmic
Topical
Poor gram (+) coverage and anaerobic coverage


Question 1: What determines if a bacterial organism is gram negative or gram positive?


Question 2: Why isn’t a beta lactam antibiotic or other agent that inhibits cell wall synthesis used for young healthy people with community acquired pneumonia?


Question 3: Which of the following antibiotics provides the best activity against gram negative bacteria?
  1. Daptomycin (Cubicin)
  2. Clindamycin (Cleocin)
  3. Rifampin
  4. Aztreonam


Question 4: Which pair of medications does not have cross-reactivity?
  1. Linezolid and SSRIs
  2. Aztreonam and Penicillin G
  3. Daptomycin and Statin
  4. Erythromycin and Warfarin


Answer 1: Gram positive organisms have a peptidoglycan layer
  • Gram negative organisms have a thick polysaccharide layer
Answer 2: Atypicals do not have a cell wall
Answer 3: D, the rest have gram positive coverage

Answer 4: B, both are Beta lactams

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