Review of Antibiotics

Zagorka Popovski, Pharm.D.

Clinical Pharmacist, Intensive Care

Cephalosporins

Gram + 1 st Generation •Ancef •Keflex

LESS IS MORE!!!

 Timing of pre op antibiotic is key

POPOVSKI and TEOH SCCM 1993 SAN DIEGO CA

 REDUCTION OF POST-OP ANTIBIOTICS FROM 72 HR TO 48HR  ADMINISTER PRE-OP ANTIBIOTIC IN OR  WOUND INFECTION RATE REDUCED FROM 2% TO 0.6%

Gram +

Cephalosporins

1 st Generation •Ancef •Keflex Gram + Coverage plus: •Ecoli •Proteus •Klebsiella

Gram + 1 st Generation •Ancef •Keflex

Cephalosporins

2 nd Generation •Cefuroxime •Cefamandole H Flu •Cefotetan •Cefoxitin +/- anaerobe

Gram + 1 st Generation

Cephalosporins

2 nd Generation Gram 3 rd Generation •Ancef •Keflex •Cefuroxime •Cefamandole •Ceftriaxone •Cefotaxime •Cefotetan •Cefoxitin •Ceftazidime

Gram *3 rd Generation •Ceftriaxone

Cephalosporins

Gram - Coverage Acinetobacter Serratia (CNS penetration, gram neg. alternative to amnioglycosides) •Cefotaxime •Ceftazidime •Pseudomonas Aeruginosa *not for enterobacter

Penicillins

Penicillin Ampicillin Amoxillin Cloxacillin Oxacillin Nafcillin Methicillin ®

Penicillins

Coverage •Ampicillin •Amoxicillin •Enterococcus •Ecoli •Klebsiella •Proteus •H. Flu Clavulin®=amoxicillin+clavulinic acid

Antipseudomonal Penicillins

 Piperacillin (Pipracil)  Piperacillin/Tazobactam (Tazocin)  Ticarcillin (Ticar)  Ticarcillin/Clavulante (Timentin) Gram +/- (including Pseudomonas a.) *anaerobic coverage

R R

+

 Cloxacillin  Oxacillin  Nafcillin  Methicillin

Penicillins

Carbapenems

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

Meropenem

 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

F A I L U R E Christou & Solomkin, 1990 (Intra-abdominal sepsis) AA + AMG Imipenem 5 7 15 30 A.P.A.C.H.E.

Activity of Study Agents Against Facultative Gram-Negative Bacteria Bacteria E.Coli

Enterobacter Klebsiella Proteus Pseudomonas a.

Citrobacter sp.

Other Gram Negative Breakpoint…Tobramycin 4 Imipeneim 4 Tobramycin MIC 90 4.0

1.0

1.0

1.0

4.0

16.0

2.0

Resistant 5 0 0 0 1 2 0 90 0.25

1.0

1.0

4.0

2.0

0.5

4.0

Imipenem MIC Resistant 0 0 0 1 0 0 0

Activity of Study Agents Against Common Anaerobic Bacteria Bacteria ß. Fragilis Bacteroides sp.

Clostridia sp.

Enterococci Clindamycin MIC 90 Resistant 16.0

16.0

4.0

?

?

4 90 Imipenem MIC Resistant 0.50

0.50

2.0

4.0

0 0 0 0 Breakpint…Clindamycin 2 Imipenem 4

THERAPEUTIC ANTIBIOTICS (24h) ARE NOT RECOMMENDED     CONDITIONS FOR WHICH 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

Fluoroquinolones

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

Fluoroquinolones

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

CAP Strep.

+ other gram neg atypicals

Fluoroquinolones

 Advantages  Drug Interactions (Bioavailability, IV/PO, tissue penetration) (Calcium, Iron, Magnesium) (Theophylline,Methylxanthines)  Side Effects

Aminoglycosides

 Gentamicin  Tobramycin  Amikacin

Aminoglycosides

Gentamicin Tobramycin

MIC

Serratia (Pseudomonas a.) .5

2 2 .5

 Vancomycin  Linezolid  Septra

Others

SAVING ANTIBIOTICS SAVES LIVES!!!

PRINCIPLES:  For empiric therapy, reassess at day 4, consult ID  Narrow spectrum when bacteria identified  Convert to oral therapy when possible

SAVING ANTIBIOTICS SAVES LIVES!!!

 Clinical Pulmonary Infection Score (CPIS)  Takes into account temperature,wbc,secretions,ventilation,xray  6 ( bronch and treat with 8 days

SAVING ANTIBIOTICS SAVES LIVES!!!

 BENEFITS:  Reduced use of broad spectrum agents  Reduced resistance  Reduced LOS  Reduced fungal infections  Reduced costs >$200,000

CPIS Use for Non-invasive Diagnosis of HAP/VAP

Calculate CPIS CPIS≤6 CPIS>6 Consider treatment Gram stain of Tracheobronchial (TB) secretions Recalculate CPIS daily, examine Gram stain

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Treatment according to Gram stain

2

3

Pugin J. Am Rev Respir Dis. 1991;143:1121-9. Pugin J. Minerva Anestesiol. 2002;68(4):261-5. 4 5 6 7

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CPIS Antibiotic Study

 Inclusion Criteria: – Clinical Pulmonary infection score (CPIS)  6 – Ventilated or non-ventilated  Exclusion Criteria: – – Infected with HIV  18 years of age

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4 5 Singh N, et al. Am J Respir Crit Care Med. 2000;162:505-511.

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CPIS Antibiotic Study: Trial Design

CPIS≤6 Standard Therapy (antibiotics for 10-21 days) Experimental Therapy Ciprofloxacin for 3 days CPIS calculated at 3 days CPIS ≤6

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Discontinue treatment

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

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CPIS >6 Treat as pneumonia

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CPIS Antibiotic Study: Outcomes

Deaths at 3 days CPIS >6 at 3 days Extrapulmonary infections Experimental Therapy (n=39) 0% (0/39) 21% (8/39) 18% (7/39) Standard (n=42) 7% (3/42) 23% (9/39) 15% (6/39) NS NS NS Antibiotic 28% (11/39) 97% (38/39) 0.0001

continuation >3

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: Outcomes

Experimental Therapy (n=39) 0% (0/25) Standard (n=42) 96% (24/25) Antibiotic continuation > 3 days Mean duration of antibiotics, day 3 9.8

0.0001

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

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4 5 Singh N, et al. Am J Respir Crit Care Med. 2000;162:505-511.

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FUNGAL INFECTIONS

 RISK FACTORS  TPN  Steroids  Broad spectrum antibiotics  Abdominal involvement  Immunosuppression

ANTIFUNGAL 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 ’ 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 ’ d  Echinocandins: Caspofungen (inhibit fungal cell wall synthesis)  Active against C. albicans, krusei, glabrata  cost