Bugs and Drugs:Bugs and Drugs:Solving the Antibiotic DilemmaSolving the Antibiotic Dilemma

Catherine Davis, Pharm.D.

Exempla Saint Joseph Hospital

Presentation OverviewPresentation Overview

Briefly review sensitivity testing Review advantages/disadvantages of

commonly prescribed antibiotics Provide recommendations for appropriate

indications for various antibiotics

Drug Expenditures - 2001Drug 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 Challenges in Antimicrobial SelectionSelection

Changing resistance patterns New antibiotics from which to select National Backorders!!!

– Piperacillin/tazobactam– Cefotaxime– Cefotetan – Penicillin– Cefazolin

Sensitivity TestingSensitivity TestingMinimum Inhibitory ConcentrationMinimum 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 InterpretationMIC 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:Antibiotic Selection:The Right Agent for the Right PatientThe 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

Antibiotic ClassesAntibiotic Classes

Beta-Lactams– penicillins– cephalosporins– carbapenems– monobactams

Quinolones

Aminoglycosides Glycopeptides Macrolides Miscellaneous VRE Antibiotics

Penicillins:Penicillins:Pen VK, Ampicillin, AmoxicillinPen VK, Ampicillin, Amoxicillin

Advantages good oral absorption good gram + coverage

– Enterococcus

– Streptococcus

inexpensive

Disadvantages frequent dosing increasing resistance

– gram negatives

– Strep pneumo

inactivates aminoglycosides

Penicillin, Ampicillin, Amoxicillin:Penicillin, Ampicillin, Amoxicillin:Indications for UseIndications 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’sAntiStaphylococcal PCN’sNafcillin, Oxacillin, DicloxacillinNafcillin, 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 InhibitorsBeta-Lactamase Inhibitors

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

Beta-Lactamase InhibitorsBeta-Lactamase InhibitorsAugmentin, Unasyn, Timentin, ZosynAugmentin, Unasyn, Timentin, Zosyn

Advantages stabilization against beta-

lactamases excellent broad coverage,

including anaerobes Zosyn > Timentin for

Pseudomonas Enterococcus coverage

(not Timentin)

Disadvantages GI intolerance

(Augmentin) Superinfections High cost frequent dosing E. coli resistance

increasing with Unasyn

Unasyn, Zosyn IndicationsUnasyn, Zosyn IndicationsUnasyn ZosynUnasyn 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

Cephalosporins:Cephalosporins:General SimilaritiesGeneral 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:Cephalosporins:First GenerationsFirst 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:Cephalosporins:Second GenerationsSecond 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®) , Cefotetan (Cefotan®) , Cefoxitin (Mefoxin®):Cefoxitin (Mefoxin®):Indications for UseIndications 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:Cephalosporins:Third+ GenerationsThird+ 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:Third Generation Ceph’s:Indication for UseIndication 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 CephalosporinsOral 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, STD’s– 100 - 200 mg BID

CarbapenemsCarbapenems 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

Carbapenems: Carbapenems: Ertapenem (Invanz®)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:Monobactam:Aztreonam (Azactam®)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

QuinolonesQuinolonesAnother Class with GenerationsAnother 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

Quinolones:Quinolones:“First Generations”“First Generations”

Norfloxacin, Ciprofloxacin primarily gram negative, including

Pseudomonas some atypical poor gram positive, no anaerobic Cipro - interactions with theophylline,

warfarin, phenytoin

Quinolones:Quinolones:“Second Generations”“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®)Levofloxacin (Levaquin®)Indications for UseIndications 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

Aminoglycosides:Aminoglycosides:Gentamicin, Tobramycin, AmikacinGentamicin, 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

(5-7mg/kg once daily)

NO Anaerobes - requires 02 to get into cell

dosing strategies dependent on indication toxicities well defined

Glycopeptides:Glycopeptides:VancomycinVancomycin

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

Macrolides:Macrolides:erythro-, clarithro-, azithromycinerythro-, 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

Antianaerobic AgentsAntianaerobic 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

MiscellaneousMiscellaneous

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

Antifungals: FluconazoleAntifungals: 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

Antibiotic CostsAntibiotic 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: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

Non-Formulary

New Agents for VRENew Agents for VRELinezolid (Zyvox®)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

Cost ComparisonCost 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®):Linezolid (Zyvox®):Indications for UseIndications 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

Resistance: A National ConcernResistance: 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