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Antibiotic Review rev. 08-2019Advanced Pharmacology (Chamberlain University) ANTIBIOTIC REVIEWNRHS Infectious Disease Primer

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by

Liu
in

 

SECTION 1: INHIBITORS OF CELL WALL SYNTHESIS

Penicillins:

  • Introduced in 1941 for the treatment of G(+) infections (staph/strep)
  • Newer forms developed secondary to resistance and need for G(-) coverage
  • Time-dependent (troughs more important than peaks for efficacy)
  • Penicillin-binding proteins (PBP’s) are enzymes involved in cell wall synthesis in bacterial membrane that bind beta-lactams. PBP modification is a mechanism for resistance
  • Newer drugs and combos considered broad spectrum
  • Generally short half-life (frequent dosing)
  • Specific agents
    • Natural – Pen G (IV), Pen VK (oral)
      • Primarily Strep and oral anaerobes (think dentist office), syphilis DOC
    • Penicillinase-resistant – nafcillin, methicillin, oxacillin, dicloxacillin
      • Developed for emerging resistance to PCN
      • Anti-staph agents, strep coverage not as good
    • Aminopenicillins – amoxicillin, ampicillin
      • Enhanced G(-) coverage (esp. H. flu)
    • Anti-pseudomonal penicillins – piperacillin
      • Degraded by β-lactamase
      • Does NOT typically cover VRE
    • β-lactamase inhibitor combos – Augmentin (amoxicillin/clavulanate), Unasyn (ampicillin/sulbactam), Zosyn (piperacillin/tazobactam)
      • Irreversible inhibitors of β-lactamase
      • Recovers Staph coverage
      • Recovers anaerobic coverage

Carbapenems:

  • Primaxin (imipenem/cilastatin), Merrem (meropenem), Invanz (ertapenem), doripenem?
  • “Gorillacillin” – G(+), G(-), and anaerobes including Pseudomonas (except ertapenem)
  • Generally β-lactamase resistant
  • Time-dependent
  • Seizures significant with imipenem; caution with others (inclusion bias)
  • Meropenem/vaborbactam (Vabomere) – MDR including carbapenem-resistant Enterobacteriaceae

Monobactam:

  • Azacatam (aztreonam)
  • G(-) coverage only; Pseudomonal coverage
  • No anaerobic coverage
  • No cross-sensitivity with PCNs

Cephalosporins:

  • Time-dependent
  • As generations increase, more G(-) coverage is added (up to fourth)
  • Specific agents
    • First generation – Keflex (cephalexin), Kefzol (cefazolin)
      • G(+) organisms, Proteus, E. coli, Klebsiella (PEcK)
      • Commonly used for UTIs and surgical prophylaxis
    • Second generation
      • PO: Ceclor (cefaclor), Ceftin (cefuroxime)
      • IV: cefuroxime, cefoxitin, cefotetan
      • Adds H. flu, Enterobacter, and Neisseria (HENPEcK)
      • Cefoxitin, cefotetan = anaerobic coverage (cefoxitin has no oxygen)
      • Cefuroxime should be given with food to avoid degradation by esterases
    • Third generation
      • PO: Suprax (cefixime), Vantin (cefpodoxime), Omnicef (cefdinir)
      • IV: cefotaxime, ceftriaxone, ceftazidime
      • Further extends G(-) coverage, G(+) coverage is generally inferior
      • Rocephin (ceftriaxone)
        • Long half-life (q24h dosing)
        • Excreted in bile, so no renal dose adjustments
        • “Good” CNS penetration – DOSE q12h in meningitis
        • Displaces bilirubin – caution in neonates
      • Fortaz (ceftazidime) = (+) Pseudomonas coverage
    • Fourth generation – Maxipime (cefepime)
      • G(+) and G(-) coverage
      • Pseudomonas coverage
      • Used in febrile neutropenia and as alternative to Zosyn in sepsis for PCN-allergic patients
    • “Fifth generation” – Teflaro (ceftaroline)
      • Indicated for CAP and ABSSSI
      • Gram (-) – E. coli, Klebsiella, H. flu
      • No Pseudomonal coverage
      • Not indicated for MRSA pneumonia or bacteremia, but can be seen in combination with vancomycin for persistent infections
    • Cephalosporin/beta-lactamase inhibitor combinations – ceftolozane/tazobactam (Zerbaxa) and ceftazidime/avibactam (Avycaz)
      • Zerbaxa on NRHS formulary
      • No MSSA, MRSA, enterococcus coverage
      • Reserve for resistant and MDR pathogens
      • Avycaz has activity against KPC
      • Pseudomonas coverage (Zerbaxa better for MDR Pseudomonas)
      • FDA approved for complicated UTI/pyelonephritis, HAP/VAP, resistant intra-abdominal infections

Glycopeptides:

  • Gram(+) only; MRSE and MRSA coverage
    • Vancomycin
      • PK-PD parameter: trough only vs. AUC(using trough and peak)
        • Trough = 10-15 mcg/mL for cellulitis, ABSSSI, UTIs
        • Trough = 15-20 mcg/mL for PNA, meningitis, osteomyelitis, septic arthritis, endocarditis
      • Little to no absorption orally; given PO for C. difficile colitis as PREFERRED agent
      • Red man syndrome – histamine release
        • Pre-medicate with diphenhydramine
        • Slow down infusion time
      • Nephrotoxicity not as common these days (but still a problem)
        • Increased in diabetics and patients on concomitant nephrotoxic agents such as Zosyn
    • Vibativ (telavancin)
      • Concentration dependent
      • Last line use for HAP/VAP or ABSSSI
      • BBW – teratogenic (Med Guide required)
    • Orbactiv (oritavancin)
      • Acute bacterial skin and skin structure infections (ABSSSI)
      • 1,200 mg IV single dose, infused over 3 hrs
      • Metabolized by CYP450 (drug interactions, ex. warfarin)
      • Half-life: 10.2 days
      • CI: use of IV UFH for 5 days after administration
    • Dalvance (dalbavancin)
      • ABSSSI
      • One and two-dose regimens (30 min infusion), renal dose adjustments for CrCl <30 mL/min
      • No significant drug-drug interactions
      • Half-life: 8.5 days

SECTION 2: INHIBITORS OF BACTERIAL PROTEIN SYNTHESIS

Macrolides:

  • Erythromycin, clarithromycin, azithromycin
  • “Extended” spectrum
    • Think URI’s, strep throat, COPD, and STD’s
    • G(+): Strep, Staph
    • G(-): H. flu, M. cat, N. gonorrhea
    • Atypicals: Mycoplasma, Chlamydophila, Legionella

Lincosamides:

  • Clindamycin (also lincomycin – rarely seen)
    • Gram(+) only; excellent anaerobic coverage
    • Excellent bone penetration
    • Used in PCN-allergic patients for surgical prophylaxis
    • Oral suspension tastes terrible
    • Used for “toxin sweeping”; especially with Group A Strep
    • Commonly associated with antibiotic-associated colitis

Oxazolidinones:

  • G(+) coverage
    • Zyvox (linezolid)
      • MRSA and VRE coverage
      • Used in pneumonia, ABSSSI, UTIs
      • IV to PO is 1:1 conversion, 600 mg q12h
      • MAO inhibitor
        • CI with SSRIs (risk for serotonin syndrome)
      • Monitor for myelosuppression/thrombocytopenia, increased risk > 2 weeks of therapy
    • Sivextro (tedizolid)
      • ABSSSI only, 200 mg PO once daily for 6 days
      • Still recommended to avoid MAOIs, but SSRIs (and other serotonergic drugs) appear to be okay

Tetracyclines:

  • Tetracycline, doxycycline, minocycline
  • Broad spectrum, used frequently in tick-borne illnesses, covers atypicals
    • Rickettsia, Chlamydia, Legionella, spirochetes
  • Permanent discoloration of teeth in children (get consent if less than 8 yo)
  • Chelates cations – separate from dairy, iron, etc.

Aminoglycosides:

  • Gentamicin, tobramycin, amikacin
  • Considered extended spectrum but many G(+) organisms are resistant
  • (+) Pseudomonal coverage
  • Used in pneumonia, UTIs, gynecological infections, endocarditis as synergy
  • Conventional vs. extended-interval dosing (see AG policy)
  • Concentration dependent
    • Peaks important for monitoring efficacy (4-8mcg/mL depending on disease state) and toxicity (ototoxicity)
    • Troughs important for toxicity (nephro)
      • Less than 2 mcg/mL, preferably < 1 mcg/mL
  • Post-antibiotic effect
  • Synergistic effects with PCN or vanco for Staph or Enterococci
  • Plazomicin now approved for cUTI – once daily dosing (renal adjustments), troughs only

Synercid (Quinupristin/Dalfopristin):