Bugs and Drugs: Solving the Antibiotic Dilemma

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Bugs and DrugsSolving the Antibiotic Dilemma

• Catherine Davis, Pharm.D.
• Exempla Saint Joseph Hospital

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Presentation Overview

• Briefly review sensitivity testing
• Review advantages/disadvantages of commonly
  prescribed antibiotics
• Provide recommendations for appropriate
  indications for various antibiotics

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Drug Expenditures - 2001
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Challenges in Antimicrobial Selection

• Changing resistance patterns
• New antibiotics from which to select
• National Backorders!!!
• Piperacillin/tazobactam
• Cefotaxime
• Cefotetan
• Penicillin
• Cefazolin

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Sensitivity TestingMinimum Inhibitory
Concentration

• MIC - concentration at which the growth of the
  organism is inhibited
• breakpoint is determined based on serum/tissue
  levels of respective agent
• optimum therapy is for peak to achieve gt 8 times
  the MIC
• CANNOT compare actual s between different
  classes of antibiotics

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MIC Interpretation

• If the sensitivity report indicates an MIC less
  than a specific concentration (i.e. lt8),
  antibiotic in question should achieve adequate
  concentrations to inhibit growth
• Review all agents listed as susceptible and
  select the most narrow spectrum/cost effective
  agent that will cover the organism

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Antibiotic SelectionThe Right Agent for the
Right Patient

• Infecting organism
• Susceptibility data/local resistance patterns
• Site of infection
• Duration of hospitalization/prior antibiotics
• Allergy history
• Age
• Renal/Hepatic status
• Immunologic status
• Pregnancy

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Antibiotic Classes

• Beta-Lactams
• penicillins
• cephalosporins
• carbapenems
• monobactams
• Quinolones

• Aminoglycosides
• Glycopeptides
• Macrolides
• Miscellaneous
• VRE Antibiotics

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PenicillinsPen VK, Ampicillin, Amoxicillin

• Advantages
• good oral absorption
• good gram coverage
• Enterococcus
• Streptococcus
• inexpensive

• Disadvantages
• frequent dosing
• increasing resistance
• gram negatives
• Strep pneumo
• inactivates aminoglycosides

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Penicillin, Ampicillin, AmoxicillinIndications
for Use

• Strep infections known to be PCN sensitive
• Enterococcus infections (dose 2 Gms q4h for
  ampicillin gentamicin synergy dosed)
• Necrotizing fasciitis - PCN 24 MU/day Clinda
  600mg q8h
• Renal adjust for CrCl lt30 mL/min

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AntiStaphylococcal PCNsNafcillin, Oxacillin,
Dicloxacillin

• Advantages
• excellent Staph aureus coverage
• best treatment option for serious MSSA infections
• narrow spectrum (no gram negative coverage)
• Diclox for Staph

• Disadvantages
• frequent dosing (2 Gms q4-6h)
• increasing incidence of MRSA (35 at ESJH)
• no Enterococcus coverage

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Beta-Lactamase Inhibitors

• Amoxicillin/Clavulanate (Augmentin)
• Ampicillin/Sulbactam (Unasyn)
• Piperacillin/Tazobactam (Zosyn)
• Ticarcillin/Clavulanate (Timentin)

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Beta-Lactamase InhibitorsAugmentin, Unasyn,
Timentin, Zosyn

• Advantages
• stabilization against beta-lactamases
• excellent broad coverage, including anaerobes
• Zosyn gt Timentin for Pseudomonas
• Enterococcus coverage (not Timentin)

• Disadvantages
• GI intolerance (Augmentin)
• Superinfections
• High cost
• frequent dosing
• E. coli resistance increasing with Unasyn

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Unasyn, Zosyn IndicationsUnasyn
Zosyn

• Intraabdominal prophylaxis gentamicin for E.
  coli
• Mixed infection including Enterococcus
• 1.5-3 Gms q6h

• Severe mixed infection
• workhorse ICU drug
• Ventilator associated pneumonia /- AG
• Severe diabetic foot infection suspected of
  involving mixed flora
• Narrow as soon as possible
• 3.375 Gms q6h

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CephalosporinsGeneral Similarities

• excellent penetration to tissues, including BBB
  (ceftriaxone, cefotaxime)
• coverage based on generation
• NO ENTEROCOCCUS ACTIVITY
• wide therapeutic index
• wide range of uses
• historically comprises one of the largest
  portions of antibiotic budget

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CephalosporinsFirst Generations

• most active against gram positives
• cellulitis
• good coverage against selected gram negatives (E.
  coli, Proteus, Klebsiella)
• Good option for pyelonephritis
• excellent for surgical prophylaxis (cefazolin)
• Cefazolin (Ancef) 1 Gm q8h
• Cephalexin (Keflex) higher MICs to Staph

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CephalosporinsSecond Generations

• less gram positive coverage
• additional gram negative coverage, respiratory
  pathogens (Hemophilus, Moraxella) - cefuroxime
  (Zinacef, Ceftin)
• anaerobes (anti-anaerobic agents - cefotetan,
  cefoxitin, cefmetazole)
• 75 anaerobic coverage
• intraabdominal, GYN prophylaxis

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Cefotetan (Cefotan) , Cefoxitin
(Mefoxin)Indications for Use

• Surgical Prophylaxis for intraabdominal
  infections (Cefotan 1 Gm q12h)
• Intraabdominal infections from community (no
  Enterococcus coverage)
• Diabetic foot infections (E. coli, anaerobes)

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CephalosporinsThird Generations

• additional gram negative (nosocomial) coverage,
  some gram positive, anaerobic coverage
• Pseudomonas coverage (ceftazidime, cefepime)
• excellent BBB penetration (ceftriaxone,
  cefotaxime and others)
• Good coverage against Strep and Staph (except
  ceftazidime)

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Third Generation CephsIndication for Use

• Cefepime (Maxipime), ceftazidime (Fortaz)
• Neutropenic Fever (cefepime 2 Gms q12h)
• Pseudomonas infections
• Cefotaxime (Claforan), ceftriaxone (Rocephin)
• Meningitis (cefotaxime 2 Gms q8h)
• CAP (cefotaxime 1 Gm q8-12h)
• Endocarditis with HACEK organisms or PCN
  intermediate Strep (cefotaxime 2 Gms q8h)

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Oral Cephalosporins

• 1st Generation cephalexin (Keflex)
• 500 mg TID-QID
• UTI
• 2nd Generation None Formulary
• Ceftin, Cefzil, Lorabid
• 3rd Generation cefpodoxime (Vantin)
• Oral transition for CAP, STDs
• 100 - 200 mg BID

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Carbapenems

• Imipenem/Cilastatin (Primaxin)
• excellent broad spectrum coverage but increasing
  Pseudomonas resistance
• reserve for resistant organisms, seriously ill
  patients or PCN allergy
• potential for seizures - adjust for renal status
• beta-lactamase inducer
• 500 mg q6-8h
• Meropenem (Merrem)
• less seizure risk
• fewer indications

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Carbapenems Ertapenem (Invanz)

• Recently approved agent for community infections
• Intraabdominal or complicated skin and skin
  structure infections
• No Enterococcus or Pseudomonas coverage
• 1 Gm IV q24h
• Adjust for CrCl lt30 mL/min (500 mg qd)

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MonobactamAztreonam (Azactam)

• ONLY gram-negative coverage
• moderate Pseudomonas activity
• safe to use in PCN allergic patients
• excellent safety profile
• 1 -2 Gms q8h
• Adjust for CrCl lt30 mL/min

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QuinolonesAnother Class with Generations

• excellent tissue penetration
• excellent bioavailabilty
• convenient dosing
• some resistance to Pseudomonas developing
• potential for overuse due to many factors
• avoid with sucralfate, separate from antacids

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QuinolonesFirst Generations

• Norfloxacin, Ciprofloxacin
• primarily gram negative, including Pseudomonas
• some atypical
• poor gram positive, no anaerobic
• Cipro - interactions with theophylline, warfarin,
  phenytoin

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QuinolonesSecond Generations

• Levofloxacin, Lomefloxacin, Gatifloxacin,
  Moxifloxacin
• additional gram positive and atypical coverage,
  including Strep pneumoniae
• moderate gram negative
• excellent bioavailability
• Levofloxacin - warfarin interactions
• Moxifloxacin - no Pseudomonas coverage, good
  anaerobic coverage (KP formulary)

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Levofloxacin (Levaquin)Indications for Use

• CAP, especially patients with comorbidities
• Doxycycline for pts with no comorbidities
• Complicated UTI infections (resistant to first
  generation cephs, sulfa)
• Gram negative infections in patient allergic to
  PCN (/- AG or anaerobic coverage)
• Not preferred for cellulitis (750 mg dose)
• 500 mg IV/PO qd (adjust for CrCl lt 50)
• Add metronidazole for anaerobes

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AminoglycosidesGentamicin, Tobramycin, Amikacin

• excellent gram negative coverage
• amikacin gt tobramycin gt gentamicin
• synergistic activity
• low levels for gram positive synergy (1 mg/kg)
• therapeutic levels for gram negative synergy
• (5-7mg/kg once daily)
• NO Anaerobes - requires 02 to get into cell
• dosing strategies dependent on indication
• toxicities well defined

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GlycopeptidesVancomycin

• excellent gram positive
• reserve for resistant organisms, PCN/Ceph
  allergic patients
• VRE
• GISA??
• nephrotoxicity no longer a real concern
• only monitor troughs except for select
  situations
• oral ONLY for Flagyl failures

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Macrolideserythro-, clarithro-, azithromycin

• moderate gram positives (Strep developing
  resistance - now up to 35)
• good atypical
• use for lower respiratory tract infections
• erythro and clarithro interactions
• theophylline, warfarin ( azithro)
• azithromycin - STD coverage (1 Gm x1)
• CAP 250 - 500 mg qd x 5-7 days

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Antianaerobic Agents

• Metronidazole (Flagyl)
• excellent anaerobic, first line C. difficile
• 500 mg q12h except C. diff and bowel preps
• half-life 8 hours
• Excellent bioavailability
• warfarin interaction, disulfiram reactions
• Clindamycin (Cleocin)
• gram positive, anaerobic (600 mg IV q8h max)
• Use with PCN for nec fasciitis (Gp A Strep)
• ? Pseudomembranous colitic

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Miscellaneous

• SMX/TMP (Septra, Bactrim)
• excellent tissue penetration, broad uses
• gram positive and easy gram negative
• warfarin interaction
• Some GI intolerance in elderly

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Antifungals Fluconazole

• Not effective against non-albicans strains
• Indications for use
• C. albicans from sterile body site
• C. albicans from multiple non-sterile sites
  (urine, wound, sputum)
• Prophylaxis for recurrent intraabdominal rupture
  or anastomotic leak
• Systemic infections 800 mg load, 400 mg qd
• UTI 100 mg qd x5 days
• Excellent bioavailability

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Antibiotic Costs
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New Agents for VRE

• Quinupristin/Dalfopristin (Synercid)
• Streptogramin antibiotics
• Effective against VREF (not E. faecalis), Staph
  aureus (MRSA and MSSA)
• Dosing 7.5 mg/kg q8h
• Infusion related ADRs - central line preferred
• Potential to elevate liver enzymes
• Cyt P450 3A4 interaction
• Non-Formulary

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New Agents for VRELinezolid (Zyvox)

• Oxazolidinone antibiotic
• Effective against E. faecalis E. faecium, MRSA,
  MSSA, Strep pneumo
• IV, PO, Suspension - 100 absorption
• 600 mg BID
• Thrombocytopenia (gt 2 weeks duration of therapy),
  GI intolerance
• MAOI - weak inhibitor
• Dopamine, epinephrine - adjust dose down

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Cost Comparison
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Linezolid (Zyvox)Indications for Use

• VREF
• likely will be considered preferred therapy in
  place of Synercid
• need to carefully evaluate for potential
  colonization
• MRSA Infections ONLY for Vanco intolerant
  patients
• after trial of continuous infusion /- Benadryl
  if possible
• ID Consult

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Resistance A National Concern

• Often result of inappropriate or overuse of
  antibiotics
• Significant financial impact on healthcare
• Selecting out multi-drug resistance
• Narrow coverage as soon as possible
• ? Rotation of preferred classes of antibiotics
• Dont treat colonizations or contaminations