The Five Intravenous Antibiotics You Need to Know

The Five Intravenous Antibiotics You Need to Know Ray Geyer, DO Infectious Disease Specialist Medical Director, Benefis Infection Prevention Empirical Antimicrobial Prescribing: Save the Patient and Kill the Beast! Culture/data-driven Antimicrobial de-escalation: Save the World! Empirical therapeutics: Sepsis protocols Common infection admission protocols Correct drug/correct dose Surgical prophylaxis Antibiogram data Empirical Antimicrobial Prescribing: Save the Patient and Kill the Beast! Culture/data-driven Antimicrobial de-escalation: Save the World! Precision therapeutics: Therapeutic dose monitoring Toxicity monitoring Culture susceptibility interpretation Drug peak serum level/organism MIC

Empirical Antimicrobial Prescribing: Save the Patient and Kill the Beast! Culture/data-driven Antimicrobial de-escalation: Save the World! MRSA, VRE, ESBL, KPC, C. difficile* Antibiotic-resistant organism epidemics driven entirely by prescribing practices * CDC now looks at C. difficile infection rates as a marker of hospital safety. C. difficile infection has been added to CDC s Vital Signs program, an epidemiologic project identifying the nation s greatest health risks (childhood obesity, tobacco abuse, prescription drug abuse/opioid abuse). CDI is just as lethal and has as many deaths/year as prescription opioid abuse. Empirical Antimicrobial Prescribing: Save the Patient and Kill the Beast! *Allergy history accuracy Rapid molecular diagnostics Antimicrobial stewardship Education and feedback Restricted formulary Pharmacist support Infection control Hand hygiene Isolation Environmental cleaning Culture/data-driven Antimicrobial de-escalation: Save the World! *For preoperative prophylaxis, failure to carefully determine significance of penicillin allergic has driven nationwide surge in clindamycin use and post-op C. difficile infection. Protocols are changing to penicillin anaphylaxis or cephalosporin allergic Five Intravenous Antibiotics You Need to Know 1. cefazolin 2. ceftriaxone 3. vancomycin 4. piperacillin-tazobactam (Zosyn) 5. gentamicin

Cefazolin (Ancef, Kefzol) 1 st generation cephalosporin; contains beta-lactam ring Bacterial grown is inhibited by interference with synthesis of cell wall Is bactericidal beginning at concentration 4 times the MIC of organism; duration of time that drug concentration exceeds MIC is major determinant of antibacterial activity Active against Streptococci, Staphylococci, E. coli, Klebsiella pneumoniae, Proteus mirabilis Cefazolin (Ancef, Kefzol) Excreted in urine Usual dose for normal renal function is 1-2 gm IV Q 8H For GFR 10-50 cc/min: 500 mg - 1 gm IV Q 12H For GFR <10 cc/min: 500 mg - 1 gm IV Q 24H Hemodialysis: 500 mg - 1gm after each HD No Bacteroides fragilis activity Cefazolin (Ancef, Kefzol) Excellent for treatment of skin/soft tissue infection/cellulitis, and prophylactic antibiotic of choice for clean elective surgical procedures, such as foreign body implantation, and clean contaminated procedures, such as cholecystectomy. Also excellent for uncomplicated UTI/pyelonephritis IV to PO switch = keflex (cephalexin) 1 gram PO BID

Ceftriaxone (Rocephin) 3 rd generation cephalosporin; contains beta-lactam ring Enhanced gram negative coverage and retains gram positive coverage (not MRSA) Same mechanism of action as cefazolin Active against Strep pneumoniae, beta-hemolytic Strep, Staph aureus (MSSA), Hemophilus influenzae, Neisseria meningitidis, E. coli, Kleb pneumoniae, Proteus mirabilis; not Pseudomonas. Limited antianaerobic activity. No Enterococcus activity. Ceftriaxone (Rocephin) 95% serum protein bound 50% renal and 50% hepatic excretion, no dose change needed for renal insufficiency or hemodialysis Usual dose 1 2 gm IV Q 24H; for meningitis, 2 gm IV Q 12H

Ceftriaxone (Rocephin) Major use is community-acquired pneumonia, including penicillin-resistant Pneumococci; also useful soft tissue infection, complicated UTI, intra-abd infection (with anti-bacteroides fragilis drug), meningitis, gonorrhea, Lyme disease with neurologic or cardiac involvement, typhoid fever, MSSA osteomyelitis, invasive Salmonella infections, brain abscess Ceftriaxone (Rocephin) Avoid use for Enterobacter, Citrobacter, Serratia infections causes derepression of chromosomallyencoded cephalosporinase treatment failure IV to PO switch: depends on diagnosis and susceptibility data

Vancomycin Glycopeptide antibiotic; causes inhibition of bacterial cell wall synthesis in gram+ organisms; bactericidal Broad range of activity against gram+ microorganisms; including Staphylococci, E. faecalis and some E. faecium (all serious Enterococcal infections require aminoglycoside for synergistic killing), all Streptococcus pneumoniae, all β-hemolytic and viridans Streptococci; Listeria, Bacillus, Corynebacteria, and gram+ anaerobes, such as Peptostreptococcus, Actinomyces, Clostridium sp, including C. difficile Vancomycin Resistance issues are important to understand: a) Enterococcus faecium with vancomycin resistance = VRE Mediated by Van A and Van B genes, which encode peptidoglycan cell wall with low to zero affinity for glycopeptides Van C is naturally-occurring vancomycin resistance in E. gallinarum/casseliflavus b) Van A-mediated VRE is a US healthcare epidemic Vancomycin Resistance issues are important to understand: c) VISA is vancomycin-intermediate susceptibility Staph aureus, marked by thickened cell wall and poor drug penetration to binding site; genes encode for proliferation of cell wall precursors and decreased cell wall turnover, trapping glycopeptide away from target. Cannot be identified by disc testing; requires agar or broth dilution (Vitek). VISA = Vanc MIC 2-4 µg/ml d) VRSA = Van A-mediated vancomycin resistant S. aureus; rare in US; vanc MIC 8-32 µg/ml

Vancomycin Recommend pharmacy dose management to achieve consistent trough 15-20, after loading dose of 15 mg/kg IV. Drug is only effective at serum concentration 5-10 x MIC. Pharmacists also assist with renal dose monitoring for patients with renal dysfunction, as 95% drug clearance via kidney Rapid IV infusion can produce red man syndrome - treated with antihistamines (H1 receptor antagonists) Vancomycin Oral vancomycin is nonabsorbable from gut; only indication is treatment of C. difficile infection IV vancomycin remains drug-of-choice for serious deep-seated MRSA infections, although other MRSA-active agents exist for less serious infections (linezolid, tigecycline, daptomycin, ceftaroline, doxycycline, trimethoprim-sulfa) Probably not drug-of-choice for serious MRSA pneumonia; linezolid 600 mg IV Q 12H superior for this indication Piperacillin-tazobactam (Zosyn) Piperacillin + potent β-lactamase inhibitor covers Streptococci, Staphylococci (not MRSA), Hemophilus, Enterobacteriaceae, Pseudomonas, excellent anti anaerobe agent 3.375 gm IV Q 6H for most infections (normal renal function), but 4.5 gm IV Q 6H for Pseudomonas infections

Piperacillin-tazobactam (Zosyn) Renal insufficiency dosing needed: GFR 20-40 - 2.25 gm IV Q 6H vs 3.375 gm IV Q 8H (Pseudomonas) GFR < 20-2.25 gm IV Q 8H vs 2.25 gm IV Q 6 H (Pseudomonas) Hemodialysis - extra dose of 0.75 gm IV after each HD Piperacillin-tazobactam (Zosyn) Examples of how we use Zosyn in our empiric antibiotic guidelines. Remember to de-escalate Zosyn once culture data is available Time above organism MIC is critical for expanded spectrum penicillins; dosage regimens should maintain serum levels above MIC of infecting organism for entire dosage interval. (New: Zosyn 4.5 gm IV Q 8H, each dose infused over 4 hours.) Community-Onset Intra-abdominal Infection (examples: perforated duodenal ulcer, ascending cholangitis, acute diverticulitis, acute appendicitis) Obtain blood cultures x 2 sites Consult general surgery as indicated (acute abdomen, free intraperitoneal air, etc) Penicillin non-allergic Zosyn 4.5 grams IV q6h Penicillin allergic Levaquin 750 mg IV q24h Metronidazole 500 mg IV q6h Evaluate blood cultures at day 2 and any available intra-abdominal cultures Blood and/or intra-abdominal cultures reveal specific organism with susceptibility data: change to narrow spectrum agent and consider IV to PO switch when appropriate. Duration of total antibiotic therapy varies with specific diagnosis (example: post appendectomy antibiotic therapy duration much shorter than treatment for cholangitis) Blood and/or intra-abdominal no growth: consider alternative diagnosis; consider stopping antibiotic therapy (example: evaluation for abdominal pain reveals no infection). Any questions: consult unit-based pharmacist or I.D. consult pager 454-4338 or phone 771-3435.

Hospital-Onset Skin and Skin Structure Infections/Cellulitis Most common examples: IV site related cellulitis and surgical site infection/cellulitis Empiric coverage needed for Pseudomonas aeruginosa and MRSA Obtain blood cultures x 2 sites and wound culture of any open wound Penicillin non-allergic Penicillin allergic Zosyn 4.5 grams IV q6h Aztreonam 2 grams IV q8h Vancomycin *** 15mg/kg IV x 1, Vancomycin*** 15mg/kg IV x 1, Then pharmacy dosing service then pharmacy dosing service *** if vancomycin allergic or intolerant: ***if vancomycin allergic or intolerant: then Zosyn as above then Aztreonam as above Linezolid 600 mg IV/PO q12h Linezolid 600 mg IV/PO q12h Evaluate blood and wound cultures at day 2 Blood and/or wound cultures reveal specific organism with susceptibility data: change to narrow spectrum agent; consider IV to PO switch; Anticipate total duration of antibiotic therapy = 10-14 days All cultures no growth: reconsider diagnosis (allergyrelated skin rash, inflammatory dermatitis, etc) versus continue treatment for cellulitis; consider IV to PO switch. Any questions: consult unit-based pharmacist or ID consult pager 454-4338 or phone 771-3435 Hospital Onset Urinary Tract Infection (Includes Foley catheter associated UTI; Any hospitalization within past 30 days and/or any urologic procedure within past 30 days. NOT sepsis; not an ICU admission) Order UA with micro, urine cultures, blood cultures x 2 Need empiric coverage for MRSA and Pseudomonas aeruginosa Penicillin non-allergic Penicillin allergic Zosyn 4.5 grams IV q6h Tobramycin 5 mg/kg IV q24h Vancomycin 15 mg/kg IV x 1, Vancomycin 15 mg/kg IV x 1, Then pharmacy dosing service Then pharmacy dosing service If vancomycin allergic or intolerant: Zosyn as above Linezolid 600 mg IV/PO q12h If vancomycin allergic or intolerant: Tobramycin as above Linezolid 600 mg IV/PO q12h Evaluate blood and urine cultures at day 2 Urine and/or blood cultures complete with susceptibility data: change to narrow spectrum agent; consider IV to PO switch; total duration of 10-14 days. All cultures no growth: re-evaluate diagnosis; consider stopping antibiotics Any questions: consult your unit-based pharmacist or ID consult pager 454-4338 or phone 771-3435 Healthcare-Associated and Hospital-Acquired Pneumonia (Patient not septic, not an ICU transfer; includes any hospital or ECF stay within 30 days of onset) Before antibiotics started: Order blood cultures x 2 sites and RT to induce sputum for gram stain, C+S Most likely pathogens needing coverage include: MRSA, Pseudomonas aeruginosa, and oral anaerobes Penicillin non-allergic Penicillin allergic Zosyn 4.5 grams IV q6h Aztreonam 2 grams IV q8h Vancomycin 15 mg/kg IV x 1, Vancomycin 15 mg/kg IV x 1, Then pharmacy dosing service then pharmacy dosing service Flagyl 500 mg IV/PO q8h If vancomycin allergic or intolerant: Zosyn as above Linezolid 600 mg IV/PO q12h If vancomycin allergic or intolerant Aztreonam and Flagyl as above Linezolid 600 mg IV/PO q12h Evaluate sputum and blood cultures at day 2 Sputum and/or blood cultures are complete with susceptibility data: change to narrow spectrum agent; consider IV to PO switch; total duration of therapy 10-14 days. All cultures no growth: Consider sterile aspiration pneumonia versus reconsider diagnosis; consider stopping Antibiotics. Any questions: consult your unit-based pharmacist or ID consult pager 454-4338 or phone 771-3435

Gentamicin Concentration-dependent bactericidal activity against susceptible pathogens. Rate of bacterial killing increases as antibiotic concentration increases. Bind to messenger RNA in prokaryotic ribosomes, protein synthesis cell membrane dysfunction cell death Resistance exists but generally rare RNA binding site mutations (gram neg rod resistance) and drugmodifying enzymes (loss of synergistic killing against Enterococci) Gentamicin Most active against aerobic gram neg rods (Enterobacteriaceae and Pseudomonas). MSSA is inhibited; no activity against Strep. Pneumoniae or anaerobes. Gentamicin is combined with appropriate betalactam (usually penicillin or ampicillin), or combined with vancomycin (when pen/amp allergic or resistant) for synergistic killing with viridans Strep and Enterococcus endocarditis. (Synergism: effect of drugs in combination is greater than anticipated effect of each individual drug) Gentamicin Given IV or IM or intra-cavity instillation, but no PO absorption. Crosses biologic membranes poorly, except is concentrated in proximal renal tubule epithelium and cochlear inner ear cells. 99% of drug excreted unchanged into urine

Gentamicin Main toxicity is renal, cochlear and vestibular, in that order. Nephrotoxicity = necrosis of cells of proximal tubule or acute tubular necrosis (ATN), which is reversible. Nephrotoxicity is reduced but not eliminated by once daily gent dosing. Trough gent levels should be 2. Ototoxicity tends toward irreversible deafness, due to hair cell death in organ of Corti. Vesibulotoxicity can occur by itself, or companion with ototoxicity. Presents as nausea/emesis with vertigo, and reversible in 50% patients. Gentamicin Two types dosing regimens: 1) Multiple daily dosing Loading dose in mg based on ideal body weight in kg: Females: 45 kg + 2.3 kg per inch of height over 5 feet Males: 50 kg + 2.3 kg per inch of height over 5 feet The loading dose is independent of renal function Gentamicin 1) Multiple daily dosing continued Maintenance dose for normal renal function is 1.0-1.5 mg/kg Q 8H infused over 30 minutes with desired peak 4 and trough < 2. For impaired renal function, dose % of 1.5 mg/kg Q 8H GFR 50-90 60-90% Q 8-12H GFR 10-49 30-70% Q 12H GFR < 10 20-30% Q 24-48H HD add ½ dose after HD

Gentamicin 2) Once daily administration Less nephro- and ototoxicity without compromising antibacterial efficacy (except neutropenic host) Total daily dose for normal renal function (GFR>80) is 5-7 mg/kg ideal body weight infused over one hour. Impaired renal function: GFR 60-79 4-5 mg/kg/day GFR 50-59 3-4 mg/kg/day GFR 30-49 2-3 mg/kg/day GFR 20-29 4 mg/kg/day Q 48H GFR 10-19 3 mg/kg/day Q 48H GFR < 10 or HD 2 mg/kg/day Q 48H Gentamicin 2) Once daily administration continued Peak measurements are predictably high, 20 mcg/ml Keep trough < 2 (often undetectable) Not used in endocarditis Empirical Antimicrobial Prescribing: Save the Patient and Kill the Beast! Culture/data-driven Antimicrobial de-escalation: Save the World!

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