Antibiotic Review rev. 08-2019Advanced Pharmacology (Chamberlain University)

ANTIBIOTIC REVIEWNRHS Infectious Disease Primer

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):

• G(+), G(-), MRSA
• Available only as a combination product for synergistic effect
• CYP3A4 inhibitor
• FDA indicated for skin and skin structure infections

Tygacil (tigecycline):

• Bacteriostatic
• G(-), G(+), MRSA, anaerobes
• Indicated for skin and skin structure infections, CAP, intra-abdominal infections
• BBW: increase in all-cause mortality, reserve for situations when can’t use alternatives

SECTION 3: INHIBITORS OF BACTERIAL NUCLEIC ACID SYNTHESIS

Fluoroquinolones:

• Ciprofloxacin, respiratory FQs – levofloxacin, moxifloxacin
• Highly effective against G(-) organisms and atypicals
• Pseudomonal coverage (Ciprofloxacin > levofloxacin)
• Staph coverage (Levofloxacin > ciprofloxacin)
• Prolonged QT interval
• Separate doses from calcium, iron, etc. due to chelation of cations
• Delafloxacin (Baxdela): covers MRSA and Pseudomonas, indicated for ABSSSI’s, IV/PO

Sulfamethoxazole/trimethoprim:

• Broad spectrum, including atypicals (Actinomycetes, Nocardia, Chlamydia)
• Synergistic combination
• Beware of kernicterus in neonates
• IV formulation can cause hyperkalemia
• PJP prophylaxis & treatment in immunosuppressed patients (HIV)
• Variable MRSA coverage
• DOC: Stenotrophomonas maltophilia

Rifampin:

• Main use is for mycobacteria or synergy
• Used commonly in hardware infections as it penetrates the biofilm
• Resistance develops rapidly – NEVER use alone except for prophylaxis in meningitis outbreaks
• Red-brown discoloration of stool, saliva, tears, sweat, and other body fluids

SECTION 4: MISCELLANEOUS

Flagyl (metronidazole):

• Mainly anaerobic (especially Bacteroides fragilis) and antiamebic activity
• Seen used in gynecological infections, intraabdominal infections
• Avoid concurrent EtOH (disulfiram reaction)
• Used for C. diff colitis (although not the preferred therapy now, see vancomycin PO)

Cubicin (daptomycin):

• Gram(+) coverage
• Interrupts cell membrane function by causing rapid depolarization
• Bactericidal in a concentration-dependent manner
• Dosed once a day (or q48h in CrCl < 30 mL/min)
• MRSA & VRE coverage
• Indicated for skin/skin structure infections, bacteremia, right-sided native valve IE
• NOT FOR PNEUMONIA; daptomycin chemical structure is inactivated by lung surfactants

Nitrofurantoin:

• G(+), G(-)
• Used for uncomplicated cystitis only; also seen in prophylaxis for recurrent cystitis
• Caution in CrCl < 50mL/min (probably okay down to 30 mL/min for short duration)

Dificid (fidaxomicin):

• Inhibits RNA polymerase sigma subunit resulting in inhibition of protein synthesis and cell death in susceptible organisms
• Macrolide – macrocyclic antibiotic
• Active against Clostridium difficile with minimal oral absorption
• Dose is 200 mg PO BID x 10 days for refractory C. diff infections
• Restricted to ID or GI physicians

Fosfomycin:

• Inhibits bacterial wall synthesis (bactericidal) by inactivating the enzyme, pyruvyl transferase, which is critical in the synthesis of cell walls by bacteria
• Gram(+) and Gram(-)
• Approved only for uncomplicated UTI in females (off-label use for males)
• May retain activity against ESBL producing organisms

Polymyxins: cationic detergents that bind to phospholipids and damage the bacterial cytoplasmic membrane causing leaking of intracellular substances and cell death; typically last line antibiotics

Colistin (colistimethate, polymyxin E):

• Colistimethate is the inactive prodrug which is hydrolyzed to colistin
• G(-) only; Pseudomonal coverage; no atypical coverage
• Used as nebulized inhalation treatment of Pseudomonal infection in cystic fibrosis
• Dose dependent nephrotoxicity, may cause reversible neurological disturbances
• Dose based on ideal body weight in obese patients

Polymyxin B:

• G(-) only; Pseudomonal coverage; no atypical coverage
• Dose dependent nephrotoxicity, and may cause reversible neurological disturbances

Anti-MSSA Agents:

• Tetracyclines (doxycycline)
• Oxacillin/Nafcillin/Dicloxacillin
• Amoxicillin/clavulanate
• Ampicillin/sulbactam
• 1st Generation Cephalosporins
• Rifampin (in combo only)

Anti-MRSA Agents:

• Vancomycin
• Linezolid/Tedizolid
• Daptomycin
• Telavancin/Oritavancin/Dalbavancin
• Ceftaroline
• Tigecycline
• Quinupristin/dalfopristin
• Sulfamethoxazole/trimethoprim
• Clindamycin
• Tetracyclines (doxycycline)
• Nitrofurantoin
• Rifampin (in combo only)
• Delafloxacin

Anaerobic Agents:

• Clindamycin
• Metronidazole
• Cefoxitin/Cefotetan
• Amoxicillin/clavulanate
• Ampicillin/sulbactam
• Piperacillin/tazobactam
• Meropenem/Imipenem/Ertapenem
• Moxifloxacin
• Tigecycline

Anti-Pseudomonal Agents:

• Tobramycin/Gentamicin/Amikacin/Plazomicin
• Piperacillin
• Meropenem/Imipenem
• Ceftazidime/Cefepime
• Ceftolozane/tazobactam
• Aztreonam
• Ciprofloxacin
• Levofloxacin
• Colistin, Polymyxin B