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)
  • 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

Penicillin G
Streptococcal infections
Staph aureus (susceptible)
IM/IV: 3-4 million units q 4 hours
Continuous infusion over 24 hours if normal renal function
Penicillin G Benzathine
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)
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

E. coli
Proteus (K. pneumoniae intrinsically resistant)
Enterococcus: gram (+) cocci in pairs; faecalis
Streptococcus: gram (+), viridans, pyogenes, pneumoniae, agalactiae
IV: 2 grams q 4-6 hours
Gram positive and negative coverage (limited)
Similar to Ampicillin
Better Gram (-) coverage
Anaerobes: E. coli

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

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)
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

Tazobactam (Zosyn)
Empiric or definitive therapy for Pseudomonas aeruginosa
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)

  • 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)

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
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
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
Staphylococcus (MRSA)
IV: 600 mg q 8-12 hours

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

Gram negative coverage: ESBL producing Enterobacteriaceae
IV: 1 g q 24 hours

Same as Ertapenem
Pseudomonas aeruginosa
IV: 1 g q 8 hours
IV: 2 g q 8 hours (CNS)
Broad spectrum activity, limit activity
Similar to Meropenem
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
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

(BACiiM, Bacitracin)
Gram (+) and Gram (-) activity
Staphylococcal pneumonia, aureus, epidermidis
Streptococcus pyogenes
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
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
Colistin (colistimethate sodium)
Highly resistant GNR, including Pseudomonas and Klebsiella
CRE: Carbapenem resistant Enterobacteriaceae

Multidrug resistant GN infections: pneumonia, bacteremia, sepsis, complicated UTIs
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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