Bugs and Drugs:
Solving the Antibiotic Dilemma
Catherine Davis, Pharm.D.
Exempla Saint Joseph Hospital
Presentation Overview
Briefly review sensitivity testing
 Review advantages/disadvantages of
commonly prescribed antibiotics
 Provide recommendations for appropriate
indications for various antibiotics

Drug Expenditures - 2001
Drug
Expenditures
Ondansetron (Zofran)
$320,000
Tirofiban (Aggrastat)
$313,400
IVIG
$194,500
Levofloxacin (Levaquin) $159,000
Filgrastim (Neupogen)
$149,000
Pip/Tazo (Zosyn)
$138,000
Challenges in Antimicrobial
Selection
Changing resistance patterns
 New antibiotics from which to select
 National Backorders!!!
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Piperacillin/tazobactam
Cefotaxime
Cefotetan
Penicillin
Cefazolin
Sensitivity Testing
Minimum 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 > 8
times the MIC
 CANNOT compare actual #’s between
different classes of antibiotics

MIC Interpretation
If the sensitivity report indicates an MIC
less than a specific concentration (i.e. <8),
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

Antibiotic Selection:
The Right Agent for the Right Patient
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Infecting organism
Susceptibility data/local resistance patterns
Site of infection
Duration of hospitalization/prior antibiotics
Allergy history
Age
Renal/Hepatic status
Immunologic status
Pregnancy
Antibiotic Classes

Beta-Lactams
–
–
–
–

penicillins
cephalosporins
carbapenems
monobactams
Quinolones
Aminoglycosides
 Glycopeptides
 Macrolides
 Miscellaneous
 VRE Antibiotics

Penicillins:
Pen VK, Ampicillin, Amoxicillin
Advantages
 good oral absorption
 good gram + coverage
Disadvantages
 frequent dosing
 increasing resistance
– Enterococcus
– Streptococcus

inexpensive
– gram negatives
– Strep pneumo

inactivates
aminoglycosides
Penicillin, Ampicillin, Amoxicillin:
Indications 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 <30 mL/min

AntiStaphylococcal PCN’s
Nafcillin, 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
Beta-Lactamase Inhibitors
Amoxicillin/Clavulanate (Augmentin®)
 Ampicillin/Sulbactam (Unasyn®)
 Piperacillin/Tazobactam (Zosyn®)
 Ticarcillin/Clavulanate (Timentin®)

Beta-Lactamase Inhibitors
Augmentin, Unasyn, Timentin, Zosyn
Advantages
Disadvantages
 stabilization against
 GI intolerance
beta-lactamases
(Augmentin)
 excellent broad
 Superinfections
coverage, including
 High cost
anaerobes
 frequent dosing
 Zosyn > Timentin for
 E. coli resistance
Pseudomonas
increasing with Unasyn
 Enterococcus coverage
(not Timentin)
Unasyn, Zosyn Indications
Unasyn
Zosyn
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Intraabdominal
prophylaxis +
gentamicin for E. coli
Mixed infection
including
Enterococcus
1.5-3 Gms q6h

Severe mixed infection
– workhorse ICU drug
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Ventilator associated
pneumonia +/- AG
Severe diabetic foot
infection suspected of
involving mixed flora
Narrow as soon as
possible
3.375 Gms q6h
Cephalosporins:
General 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

Cephalosporins:
First 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 MIC’s to Staph

Cephalosporins:
Second 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
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)

Cephalosporins:
Third+ 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)

Third Generation Ceph’s:
Indication 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)
Oral Cephalosporins

1st Generation: cephalexin (Keflex®)
– 500 mg TID-QID
– UTI
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2nd Generation: None Formulary
– Ceftin®, Cefzil®, Lorabid®
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3rd Generation: cefpodoxime (Vantin®)
– Oral transition for CAP, STD’s
– 100 - 200 mg BID
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
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Meropenem (Merrem®)
– less seizure risk
– fewer indications
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 <30 mL/min (500 mg qd)

Monobactam:
Aztreonam (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 <30 mL/min
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Quinolones
Another 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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Quinolones:
“First 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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Quinolones:
“Second 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)

Levofloxacin (Levaquin®)
Indications for Use

CAP, especially patients with comorbidities
– Doxycycline for pts with no comorbidities
Complicated UTI infections (resistant to
first generation ceph’s, 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 < 50)
 Add metronidazole for anaerobes
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Aminoglycosides:
Gentamicin, Tobramycin, Amikacin

excellent gram negative coverage
– amikacin > tobramycin > gentamicin

synergistic activity
– low levels for gram positive synergy (1 mg/kg)
– therapeutic levels for gram negative synergy
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(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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Glycopeptides:
Vancomycin
excellent gram positive
 reserve for resistant organisms, PCN/Ceph
allergic patients
 VRE
 GISA??
 nephrotoxicity no longer a real concern
 only monitor trough’s except for select
situations
 oral ONLY for Flagyl failures
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Macrolides:
erythro-, 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)
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azithromycin - STD coverage (1 Gm x1)
– CAP: 250 - 500 mg qd x 5-7 days
Antianaerobic Agents
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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
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Clindamycin (Cleocin®)
– gram positive, anaerobic (600 mg IV q8h max)
– Use with PCN for nec fasciitis (Gp A Strep)
– ? Pseudomembranous colitic
Miscellaneous
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SMX/TMP (Septra®, Bactrim®)
–
–
–
–
excellent tissue penetration, broad uses
gram positive and “easy” gram negative
warfarin interaction
Some GI intolerance in elderly
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
Antibiotic
Cost/Day
Cefotetan 1-2 Gm q12h
$16 - $32
Unasyn 3 Gm q6h
$45
Zosyn 3.375 Gm q6h
$48
Levoflox 500 mg PO/IV qd
$6 / 15
Ertapenem 1 Gm IV qd
$37
Flagyl 500 mg IV q12h
$3.10
Primaxin 500 mg q6h
$83.56
Diflucan 400 mg PO/IV qd
$19 / 100
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 ADR’s - central line preferred
– Potential to elevate liver enzymes
– Cyt P450 3A4 interaction
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Non-Formulary
New Agents for VRE
Linezolid (Zyvox®)
Oxazolidinone antibiotic
 Effective against E. faecalis & E. faecium,
MRSA, MSSA, Strep pneumo
 IV, PO, Suspension - 100% absorption
 600 mg BID
 Thrombocytopenia (> 2 weeks duration of
therapy), GI intolerance
 MAOI - weak inhibitor
 Dopamine, epinephrine - adjust dose down
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Cost Comparison
Agent/Dose
Cost/Day
Vancomycin 1 Gm q12h
$8.14
Linezolid 600 mg PO q12h
$85.00
Linezolid 600 mg IV q12h
$115.00
Synercid 500 mg q8h
$250.00
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
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ID Consult
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
 Don’t treat colonizations or contaminations
