Review of AntibioticsReview of Antibiotics

Zagorka Popovski, Pharm.D.

Clinical Pharmacist, Intensive Care

CephalosporinsCephalosporins

Gram +

1st Generation

•Ancef

•Keflex

LESS IS MORE!!!LESS IS MORE!!!

Timing of pre op antibiotic is key

POPOVSKI and TEOHPOPOVSKI and TEOHSCCM 1993 SAN DIEGO CASCCM 1993 SAN DIEGO CAREDUCTION OF POST-OP

ANTIBIOTICS FROM 72 HR TO 48HRADMINISTER PRE-OP ANTIBIOTIC IN

ORWOUND INFECTION RATE REDUCED

FROM 2% TO 0.6%

CephalosporinsCephalosporins

Gram + Gram + Coverage plus:

1st Generation •Ecoli

•Ancef •Proteus

•Keflex •Klebsiella

CephalosporinsCephalosporins

Gram + 1st Generation 2nd Generation

•Ancef •Cefuroxime •Keflex •Cefamandole

•Cefotetan +/- anaerobe•Cefoxitin

H Flu

CephalosporinsCephalosporins

Gram + Gram -

1st Generation 2nd Generation 3rd Generation

•Ancef •Cefuroxime •Ceftriaxone

•Keflex •Cefamandole •Cefotaxime

•Cefotetan •Ceftazidime

•Cefoxitin

CephalosporinsCephalosporins Gram - Gram - Coverage *3rd Generation Acinetobacter

Serratia •Ceftriaxone (CNS penetration, gram neg.

alternative to amnioglycosides)•Cefotaxime

•Ceftazidime •Pseudomonas Aeruginosa

*not for enterobacter

PenicillinsPenicillins

Penicillin Ampicillin Cloxacillin

Amoxillin Oxacillin

Nafcillin

Methicillin

®

PenicillinsPenicillins Coverage

•Ampicillin •Enterococcus•Amoxicillin •Ecoli

•Klebsiella•Proteus•H. Flu

Clavulin®=amoxicillin+clavulinic acid

Antipseudomonal PenicillinsAntipseudomonal Penicillins

Piperacillin (Pipracil)Piperacillin/Tazobactam (Tazocin)Ticarcillin (Ticar)Ticarcillin/Clavulante (Timentin)

Gram +/- (including Pseudomonas a.)

*anaerobic coverage

+

R

R

PenicillinsPenicillins

CloxacillinOxacillinNafcillinMethicillin

CarbapenemsCarbapenems

Imipenem + Cilastatin (Primaxin)Meropenem (Merrem)Ertapenem (Invanz)

MeropenemMeropenem

Very broad spectrum Gram negative including pseudomonas gram positive including staph and enterococcus Anaerobes

Indicated for “high-severity” intra-abdominal infections

Replaced imipenem//cilastatin at HHS

5 7 15 30

FAILURE

A.P.A.C.H.E.

Imipenem

AA + AMG

Christou & Solomkin, 1990

(Intra-abdominal sepsis)

Activity of Study Agents Against Activity of Study Agents Against Facultative Gram-Negative BacteriaFacultative Gram-Negative Bacteria

Bacteria

TobramycinMIC

ImipenemMIC

90 Resistant90 Resistant

E.Coli

Enterobacter

Klebsiella

Proteus

Pseudomonas a.

Citrobacter sp.

Other Gram Negative

Breakpoint…Tobramycin 4

Imipeneim 4

4.0

1.0

1.0

1.0

4.0

16.0

2.0

5

0

0

0

1

2

0

0.25

1.0

1.0

4.0

2.0

0.5

4.0

0

0

0

1

0

0

0

Activity of Study Agents Against Common Activity of Study Agents Against Common Anaerobic BacteriaAnaerobic Bacteria

Bacteria

ClindamycinMIC

ImipenemMIC

90 Resistant90 Resistant

ß. Fragilis

Bacteroides sp.

Clostridia sp.

Enterococci

Breakpint…Clindamycin 2

Imipenem 4

16.0

16.0

4.0

-

?

?

4

-

0.50

0.50

2.0

4.0

0

0

0

0

CONDITIONS FOR WHICH CONDITIONS FOR WHICH THERAPEUTIC ANTIBIOTICS (24h) ARE THERAPEUTIC ANTIBIOTICS (24h) ARE

NOT RECOMMENDEDNOT RECOMMENDED Traumatic and iatrogenic enteric perf’n operated

on within 12h Gastroduodenal perf’n operated on within 24h Acute/gangrenous appendicitis without perf’n Acute/gangrenous cholecyswtitis without perf’n Transmural bowel necrosis from

embolic,thrombotic or obsstructive vascular occlusion without perf’n or established peritonitis or abcess

FluoroquinolonesFluoroquinolones

Nalidixic acid (NegGram)Ciprofloxacin (Cipro)Norfloxacin (Noroxin) Levofloxacin (Levaquin)Gatifloxacin (Tequin)Moxifloxacin (Avelox)

FluoroquinolonesFluoroquinolones

Ciprofloxacin (Cipro) - Ps. a.Norfloxacin (Noroxin)Levofloxacin (Levaquin) Gatifloxacin (Tequin) Moxifloxacin (Avelox)

CAP

Strep.

+ other gram neg atypicals

FluoroquinolonesFluoroquinolones

Advantages (Bioavailability, IV/PO, tissue penetration)

Drug Interactions (Calcium, Iron, Magnesium)

(Theophylline,Methylxanthines)

Side Effects

AminoglycosidesAminoglycosides

Gentamicin TobramycinAmikacin

Aminoglycosides

MIC Serratia (Pseudomonas a.)

Gentamicin .5 2

Tobramycin 2 .5

OthersOthers

VancomycinLinezolidSeptra

SAVING ANTIBIOTICS SAVES SAVING ANTIBIOTICS SAVES LIVES!!!LIVES!!!

PRINCIPLES:For empiric therapy, reassess at day 4,

consult IDNarrow spectrum when bacteria identifiedConvert to oral therapy when possible

SAVING ANTIBIOTICS SAVES SAVING ANTIBIOTICS SAVES LIVES!!!LIVES!!!

Clinical Pulmonary Infection Score (CPIS)Takes into account

temperature,wbc,secretions,ventilation,xray</- 6 ( treat with 3 days levofloxacin or

cefotaxime) >6 ( bronch and treat with 8 days

SAVING ANTIBIOTICS SAVES SAVING ANTIBIOTICS SAVES LIVES!!!LIVES!!!

BENEFITS:Reduced use of broad spectrum agentsReduced resistanceReduced LOSReduced fungal infectionsReduced costs >$200,000

CPIS Use for Non-invasive CPIS Use for Non-invasive Diagnosis of HAP/VAP Diagnosis of HAP/VAP

CPIS≤6CPIS≤6CPIS≤6CPIS≤6

Consider treatmentConsider treatmentConsider treatmentConsider treatment

Calculate CPISCalculate CPIS

CPIS>6CPIS>6CPIS>6CPIS>6

Gram stain of Gram stain of Tracheobronchial (TB) Tracheobronchial (TB)

secretionssecretions

Gram stain of Gram stain of Tracheobronchial (TB) Tracheobronchial (TB)

secretionssecretions

Treatment accordingTreatment according to Gram stainto Gram stain

Treatment accordingTreatment according to Gram stainto Gram stain

Recalculate CPIS daily, Recalculate CPIS daily, examine Gram stainexamine Gram stain

Recalculate CPIS daily, Recalculate CPIS daily, examine Gram stainexamine Gram stain

Pugin J. Am Rev Respir Dis. 1991;143:1121-9. Pugin J. Minerva Anestesiol. 2002;68(4):261-5.

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CPIS Antibiotic StudyCPIS Antibiotic Study

Inclusion Criteria:– Clinical Pulmonary infection score (CPIS) 6– Ventilated or non-ventilated

Exclusion Criteria:– Infected with HIV 18 years of age

Singh N, et al. Am J Respir Crit Care Med. 2000;162:505-511.

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CPIS Antibiotic Study: CPIS Antibiotic Study: Trial DesignTrial Design

CPIS≤6CPIS≤6

Standard Standard TherapyTherapy

(antibiotics for (antibiotics for 10-21 days)10-21 days)

Standard Standard TherapyTherapy

(antibiotics for (antibiotics for 10-21 days)10-21 days)

Experimental Experimental TherapyTherapy

Experimental Experimental TherapyTherapy

Ciprofloxacin for 3 daysCiprofloxacin for 3 daysCiprofloxacin for 3 daysCiprofloxacin for 3 days

CPIS >6CPIS >6CPIS >6CPIS >6

Treat as Treat as pneumoniapneumonia

Treat as Treat as pneumoniapneumonia

Singh N, et al. Am J Respir Crit Care Med. 2000;162:505-11.

CPIS ≤6CPIS ≤6CPIS ≤6CPIS ≤6

Discontinue Discontinue treatmenttreatment

Discontinue Discontinue treatmenttreatment

CPIS calculated at 3 days

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CPIS Antibiotic Study: CPIS Antibiotic Study: OutcomesOutcomes

Experimental Therapy

(n=39)

Standard Therapy (n=42)

p Value

Deaths at 3 days 0% (0/39) 7% (3/42) NS

CPIS >6 at 3 days 21% (8/39) 23% (9/39) NS

Extrapulmonary infections

18% (7/39) 15% (6/39) NS

Antibiotic continuation >3 days

28% (11/39) 97% (38/39) 0.0001

Data for patients with entry CPIS 6 subject to standard and experimental therapy

Singh N, et al. Am J Respir Crit Care Med. 2000;162:505-511.

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CPIS Antibiotic Study: CPIS Antibiotic Study: OutcomesOutcomes

Experimental Therapy

(n=39)

Standard Therapy (n=42)

p Value

Antibiotic continuation > 3 days

0% (0/25) 96% (24/25) 0.0001

Mean duration of antibiotics, day

3 9.8 0.0001

Mean cost $259 $640 0.0001

Data for patients with CPIS 6 at the 3-day evaluation point and no extrapulmonary infections

Singh N, et al. Am J Respir Crit Care Med. 2000;162:505-511.

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CPIS Antibiotic Study: CPIS Antibiotic Study: ConclusionsConclusions

Prolonged (i.e. >3 days) use of antibiotics in patients with an initial CPIS ≤6 may be unnecessary and inappropriate

Singh N, et al. Am J Respir Crit Care Med. 2000;162:505-511.

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FUNGAL INFECTIONSFUNGAL INFECTIONS

RISK FACTORSTPNSteroidsBroad spectrum antibioticsAbdominal involvementImmunosuppression

ANTIFUNGAL AGENTSANTIFUNGAL AGENTS

Polyenes: Amphotericin B (binds to sterols and disrupts barrier resulting in leakage of intracellular contents

For hemodynamically unstable, systemic infections

Adverse effects may limit treatment

ANTIFUNGAL AGENTS cont’dANTIFUNGAL AGENTS cont’d

Azoles: Fluconazole, voriconazole, itraconazole (inhibit p450-mediated 14-alpha demethylase in the sterol)

Good activity vs C. albicans, resistance to Krusei, Glabrata

Numerous drug interactions

ANTIFUNGAL AGENTS cont’dANTIFUNGAL AGENTS cont’d

Echinocandins: Caspofungen (inhibit fungal cell wall synthesis)

Active against C. albicans, krusei, glabratacost