Interior Health Pharmacy Resident Kootenay Lake Hospital Sukhjinder Sidhu Interior Health Pharmacy Resident Kootenay Lake Hospital

Terminology Empiric therapy Prophylactic therapy Treatment of an infection before specific culture information has been reported or obtained Prophylactic therapy Treatment with antibiotics to prevent an infection

Terminology Bacteriostatic Bactericidal Stop growth of bacteria Kill bacteria www.amrls.cvm.msu.edu

Terminology Concentration-dependent killing Time-dependent killing Eradicate bacteria by achieving high concentrations at the binding site Aiming for concentrations that are > 10 x above MIC Ex: aminoglycosides, fluoroquinolones Time-dependent killing Antimicrobial activity best when drug concentration remains constantly above MIC Aiming for concentrations that are above MIC > 50% of the dosing interval Ex: penicillins, cephalosporins, carbapenems, clindamycin, vancomycin

Terminology Broad spectrum Narrow spectrum Active on a larger number of Gram-positive and Gram-negative bacteria Narrow spectrum Active on smaller number of bacterial species Collateral damage = antimicrobial resistance; adverse effects www.amrls.cvm.msu.edu

Broad vs. Narrow Cloxacillin Amoxcillin Penicillin G Nitrofurantoin Cephalexin Metronidazole Amox/Clav Fluoroquinolones Ceftriaxone Vancomycin Linezolid Macrolides Aminoglycosides Sulfonamides Tetracyclines Cefazolin Clindamycin Carbapenems Pip/Tazo

Antibiotic Step Down Narrow the antibiotic spectrum once culture and susceptibility are available Step down is an important component of antibiotic therapy because it can reduce cost and toxicity and prevent the emergence of antimicrobial resistance Antibiotic Oral Absorption (%) Amoxicillin 80% Ciprofloxacin 80 Clindamycin 90 Metronidazole 100 Moxifloxacin

Penicillins Natural penicillins Penicillinase-resistant Penicillin G Penicillin V Penicillinase-resistant Cloxacillin Penicillin plus β-lactamse inhibitors Amoxicillin-clavulinic acid Piperacillin-tazobactam Aminopenicillins Amoxcilin Ampicillin Ureidopenicillins Piperacillin ** B-lactamase inhibitors have no antibacterial action

Penicillins Inhibit bacterial cell wall synthesis Used for prevention and treatment of infections caused by Streptococcus, Enterococcus, Staphylococcus spp. DO NOT COVER MRSA Absorption of oral penicillins much improved on empty stomach Taken with food minimizes GI upset Mechanisms of resistance Inactivation by b-lactamases Modification of target PBPs Impaired penetration of drug to target PBPs Efflux pump mechanism to remove drug

Penicillins Generally non-toxic Side effects: GI upset nausea, vomiting, diarrhea, abdominal pain Pseudomembranous colitis broad spectrum agents Rash Anaphylaxis

Cephalosporins First Generation Second Generation Third Generation Cefazolin Cephalexin Second Generation Cefuroxime Third Generation Ceftazidime Ceftriaxone Cefixime Fourth Generation Cefepime

Cephalosporins Structurally and pharmacologically related to penicillins Inhibits cell wall synthesis 1st gen: mostly active against Gram + bacteria Pneumococci, streptococci, staphylococci 2nd gen: more active against Gram – bacteria E. coli, K. pneumoniae, H. influenzae 3rd gen: most active against Gram – bacteria 4th gen: extended spectrum of activity against both Gram + and – bacteria DO NOT COVER ENTEROCOCCUS or MRSA

Cephalosporins Relatively safe Side effects: GI upset nausea, vomiting, diarrhea, abdominal pain Pseudomembranous colitis broad spectrum agents Rash Super infections Anaphylaxis Hematological long term use

Carbapenems Imipenem, meropenem, ertapenem Inhibit cell wall synthesis Most broad spectrum activity of all antimicrobials Active against Gram + and – bacteria Side effects: GI upset nausea, vomiting, diarrhea Rash Seizures  those with compromised renal function Hematological eosinophilia, neutropenia Nephrotoxicity secondary to metabolite

Vancomycin Inhibits cell wall synthesis at different site than β-lactams Active against Gram + bacteria only Use restricted for MRSA and Clostridium difficile Always given IV, except for treatment of antibiotic associated enterocolitis Must give over of at least 1 hour to minimize risk of “red man syndrome” Red man syndrome = sudden drop in BP with flushing &/or rash on face, neck, chest and upper extremities

Vancomycin Troughs are taken within 30 min prior to dose Side effects: Ototoxicity at supratherapeutic doses of > 80 mg/mL Nephrotoxicity Fever, chills, phlebitis at infusion site

Sulfamethoxazole/Trimethoprim Prevent bacteria from synthesizing folic acid thereby disrupting DNA synthesis Active against both Gram + and – bacteria Mostly used in uncomplicated UTIs, and some respiratory infections Side effects: GI upset nausea, vomiting, diarrhea Skin rashes, photosensitivity Hematologic when used for long durations

Fluoroquinolones Ciprofloxacin, levofloxacin, moxifloxacin Inhibit bacterial DNA synthesis Broad spectrum of activity against Gram + and – bacteria Well absorbed orally Concentrations achieved after PO dose are comparable to those with IV dose Not recommended for use in children or pregnancy

Fluoroquinolones Absorption limited when administered within 2 hours of cations aluminum, magnesium, calcium, iron, zinc Side effects: GI upset nausea, vomiting, diarrhea, abdominal pain Pseudomembranous colitis with ciprofloxacin Rash, photosensitivity, pruritus

Aminoglycosides Gentamicin, tobramycin Inhibit bacterial protein synthesis As single agent active against Gram – bacteria Used with other agents, some Gram + synergy Only administered IV Troughs are taken within 30 min prior to dose Usually obtained when dosing q8h

Aminoglycosides Side effects: Nephrotoxicity irreversible Ototoxicity irreversible Skin rash Fever Paresthesia

Tetracyclines Tetracycline, doxycycline, minocycline Inhibit bacterial protein synthesis Some Gram + and some Gram – bacteria coverage, but many strains resistant Used primarily for infections caused by susceptible Rickettsia, Chlamydia, Mycoplasma and other uncommon bacteria Avoid use in young children and pregnancy

Tetracyclines Decreased absorption when administered with dairy products, antacids, and iron salts Space by at least 2 hours Side effects: GI upset nausea, vomiting, diarrhea Esophagitis and esophageal ulcers swallow with lots of water and avoid laying down for at least 30 min Photosensitivity, rash

Macrolides Azithromycin, erythromycin, clarithromycin Inhibit bacterial protein synthesis Active against Gram + bacteria and atypical pathogens Mycoplasma, Chlamydophila, Legionella Numerous drug interactions with clarithromycin inhibits metabolism Side effects: GI upset nausea, vomiting, abdominal cramping Especially with erythromycin

Clindamycin Inhibits bacterial protein synthesis Activity against Gram + and anaerobic bacteria Side effects: GI upset nausea, vomiting, diarrhea Pseudomembranous colitis** Skin rashes

Metronidazole Inhibits protein synthesis Activity against anaerobic bacteria Treatment of choice for C. difficile Side effects: GI upset nausea, vomiting Metallic taste

Nitrofurantoin Mechanism not fully understood Used primarily for lower UTIs caused by E. coli and Enterococcus, Not to be used in pyelonephritis Take with meals to improve absorption Side effects: Discolored urine (brown)