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OVERVIEW OF ANTIMICROBIALS Prakash Shah, Pharm.D Clinical Pharmacy Specialist, Infectious Diseases Beaumont Hospital – RO 2015 OBJECTIVES z Understand the differences between various classes of antibacterial agents z List various mechanisms of resistance z Define Redman syndrome z Given a specific antibiotic, list it’s common side effect z Define the optimum administration time of antibiotic for surgical prophylaxis ANTIMICROBIAL ROLE z Three basic roles: A) To treat the infecting organisms whose susceptibility is known B) As empirical treatment for presumed infns C) To prevent infections – Surg prophylaxis PRINCIPLES OF ANTI-INFECTIVE THERAPY COMBINATION THERAPY z To broaden the spectrum of coverage y intra-abdominal infections (amp/metro/gent) z Synergism y Enterococcal endocarditis (penicillin & gentamicin) z Preventing Resistance y TB (INH + rifampin) z Disadvantages of combination therapy y potential additive nephrotoxicity (gent +vanco) y inactivation - aminoglycosides by PCNS in renal pts. PRINCIPLES OF ANTI-INFECTIVE THERAPY Failure of Antimicrobial Therapy y Drug- related: ______________ y Host factors x _________________ x _________________ x _________________ x _________________ y Microorganisms (related) ______________ ___________________________________ Requirements for Antimicrobial Activity Porin Proteins Antibiotics 2. Penetrate Cell 1. Reach site of infection 3. Reach Target and Kill Organism PBPs (Proteins) Nucleus Ribosomes Bacterium Mechanisms of Resistance Porin Channels (Gram-negatives) •Decreased Permeability •Drug Efflux •Drug Inactivation •Altered Target Porin channels closed or decreased number Antibiotics (Proteins) Nucleus Ribosomes Antibiotics Bacterium Example: Pseudomonas Beta-lactam Allergy z Allergic reaction- principal toxicity of beta-lactams (pcns, cephalosporins) z Allergic reactions occurs in 7-40/1000 treatment cases z About 1/2 of all allergic reactions occurring in hospitalized patients are attributable to beta-lactams Antimicrobial Agents z z z z z z z z Sulfonamides Penicillins Cephalosporins Aminoglycosides Macrolides Lincosamides Quinolones Tetracyclines z z z z z z z Glycylcyclines Glycopeptides Nitroimidazole Streptogramins Oxazolidinones Nitrofurantoins Miscellaneous Sulfonamides and Trimethoprim TMP/SMX (Bactrim) z A synergistic combination, very commonly used z MOA - generally bactericidal; it acts by sequential blockade of folic acid enzymes in the synthesis pathway sulfa TMP z PABA----//-------> DHFA-----//---->THFA -- --FA Sulfonamides and Trimethoprim z z z z z z TMP/SMX (Bactrim) Bactericidal when combined o/w bacteriostatic Dosage forms - nearly every route (topical, ophthalmic, intestinal sulfas, systemic - IV, PO) Distribution- Widely distributed Elimination - Renal SE- N,V,D, hypersensitivity, hematologic, crystalluria Use - UTI, CA-MRSA SSTI, PCP, Stenotrophomonas maltophilia, etc PENICILLINS Natural Penicillins (aqueous PCN G, procaine PCN G, Benzathine PCN G and oral PCNs) z MOA - Inhibits PBPs inhibiting bacterial cell wall synthesis z Bactericidal z Distribution - Widely distributed z Elimination - mostly renal z SE - allergic reaxn, rash, GI, hematologic PENICILLINS PENICILLINASE-RESISTANT PENICILLIN Nafcillin, Oxacillin, Methicillin DOC- For penicillinase producing S. aureus Widely distributed Metabolism - Liver SE - N,V,D, Hematologic, Hypersensitivity reaxn (interstitial nephritis) z Use - Cellulitis, Osteomyelitis, Endocarditis, Pneumonia z z z z PENICILLINS Aminopenicillins Ampicillin, Amoxicillin z z z z z DOC for enterococcus Distribution - Widely distributed Elimination - Renal SE - GI, hematologic, hypersensitivity reaxn Use- Endocarditis, Meningitis, Otitis Media, UTI PENICILLINS z Antipseudomonal PCNs: carboxypenicillins y Ticarcillin (active against serious GNB including PSA, Enterobacter, Serratia, and Proteus) x high sodium content z Antipseudomonal PCNs: Ureidopenicillins y Piperacillin (most potent), y low sodium content z Piperacillin more potent against PSA vs ticarcillin PENICILLINS ß-lactam/ ß-lactamase inhibitor combos y Unasyn (ampicillin/sulbactam) y Zosyn (Piperacillin/tazobactam) y Timentin (Ticarcillin/Clavulanate) y The ß-lactamase inhibitors offer an advantage against GPO (MSSA, MSSE) & GNB (E. coli, K.pneumo, N, meningitidis, P. mirabilis, H. flu, M. cat, and Gram-neg anaerobes (B. fragilis, B. fragilis gp) PENICILLINS OVERALL COMPARISON OF ß-LACTAM/ ßLACTAMASE INHIBITORS z Timentin = Unasyn = Zosyn for Staphylococci z Timentin/Zosyn>Unasyn for enterobacteriaceae (Citrobacter, Enterobacter, E. coli, Klebsiella, Morganella, Proteus, Salmonella, Serratia, etc) z Pseudomonas… Zosyn > Timentin z S. maltophilia… Timentin > Zosyn z Enterococci… Unasyn > Zosyn > Timentin CEPHALOSPORINS z An improved spectrum of antibacterial activity, better PK properties, Concentration-independent z MOA: Bactericidal, binds to PBP enzymes preventing cell wall synthesis z Structurally similar to PCN, 1-7% cross reactivity. z Avoid in patients with high grade allergic reactions to PCNs. z Use cautiously in patients with delayed or mild reactions CEPHALOSPORINS Based on their spectrum of activity, cephs can be broadly categorized into 5 generations z First Generation Cephalosporins - Cefazolin (Ancef, Kefzol) z Second Generation Cephalosporins - cefuroxime, cefamandole, cefotetan, cefoxitin, cefmetazole z Third Generation Cephalosporins - Cefotaxime, Ceftriaxone, Ceftazidime, Ceftizoxime, Cefobid z Fourth Generation Cephalosporins – Cefepime z Newest – Ceftaroline (Teflaro) First Generation Cephalosporins Better activity against gram-positive bacteria and less gram-neg activity z Use: Cellulitis, UTI, Osteo, Surgical prophylaxis z eg. Cefazolin (Kefzol, Ancef)- very well tolerated, longer t1/2 allows less frequent dosing z Cost: $ CEPHALOSPORINS Second Generation Cephalosporins z 2 groups within this generation of cephs different spectrum of activity & SE profile z “true” cephs - cefamandole, cefuroxime similar to 1st gen against GPC, MSSA. Incr activity against some GN bacteria z Use: RTI (community acquired), UTI z WBH: Cefuroxime z Cost: $ Second Generation Cephalosporins (contd) Cephamycins - cefoxitin, cefotetan, cefmetazole Less active against GPC but better against GN bacteria and active against most anaerobes z Use: Intra-abdominal infns, Surg Prophylaxis,etc z SE: Contains a side-chain which can predispose a patient to hypoprothrombinemia and bleeding by disturbing synthesis of Vit-k dependent clotting factors in pts with certain risk factors. z RF - renal, hepatic dzs, poor nutrition, elderly, cancer, wafarin Third Generation Cephalosporins z Improved activity against hospital acquired gram-neg bacteria including Pseudomonas aeur. (ceftazidime>cefoperazone) z Should be avoided for Enterobacter sp. (may become resistant on therapy) z Less active against staph than 1st & 2nd gen z Highly active against Strep. Pneumoniae (Ceftriaxone & Cefotaxime) z None active against MRSA, Enterococci, etc. Third Generation Cephalosporins Uses Cefotaxime: CAP, bacterial meningitis, other infns Ceftriaxone: CAP, bacterial meningitis, Osteo y long t1/2 , biliary elimination, high PB Ceftazidime: Very active against PSA, poor against gram-positive. Low protein binding, renally eliminated Fourth Generation Cephalosporin z z z z z Cefepime Rapidly crosses the outer membrane of GNB Excellent activity against Enterobacteriaceae and Pseudomonas aeruginosa = ceftazidime Better Gram-positive activity than ceftazidime Weak inducer of β-lactamases so less likely to produce resistance unlike ceftazidime Widely distributed in the body Cefepime z Renally excreted z Substituted for aminoglycosides (gent/tobra) to avoid toxicity z Dosed twice a day except when treating Pseudomonas z Uses: CAP, HCAP, Febrile neutropenic patients, Meningitis, Skin and skin structure infections, UTI Ceftaroline (Teflaro) z Broad-spectrum cephalosporin with GN as well as GP activity including MRSA z FDA approved in Oct 2010 z Indications: ABSSSI, CABP z Restricted to ID only z Usual dose: 600 mg q 12 hours (IV) over 1 hour & renal adjustment required z SE: GI, HA, rash CEPHALOSPORINS ADVERSE EFFECTS z Overall, Cephs have a low incidence of SE z Thrombophlebitis: 1-5% z Hypersensitivity reaxns: Anaphylaxis (rare) y Rash: 1-3% y Hematologic reaxns: eosinophilia, neutropenia, thrombocytosis, hypoprothrombinemia y GI: Diarrhea (2-5%), biliary tract sludge y Nephrotoxicity: Rare CEPHALOSPORINS ADVERSE EFFECTS z Cefamandole, cefotetan, cefoperzone, moxalactam, cefmetazole have methylthiotetrazole (MTT) side-chain z Associated with hypoprothrombinemia and bleeding in patients with risk factors (renal dzs, hepatic dzs, poor nutrition, elderly, cancer, wafarin) Zerbaxa (Ceftolozane-tazobactam) FDA Approved – 12/19/14 z Indications – Comp. UTIs including pyelo and in combn with metronidazole for cIAI z Excellent activity against PSA z Similar efficacy when compared to meropenem for cIAI and levofloxacin for cUTI except in pts with renal impairment z Reduced efficacy in elderly with cIAI z Usual dose: 1.5 g q 8 hours (~$250/day) z ADR – N,D,HA, Insomnia, etc Cephalosporins (Oral) 1st gen: Cefadroxil (Duricef) Cephalexin (Keflex) 2nd gen: Cefaclor (Raniclor) Cefprozil (Cefzil) Cefuroxime (Ceftin) 3rd gen: Cefdinir (Omnicef) Cefditoren Spectracef) Cefixime (Suprax) Cefpodoxime (Vantin) Ceftibuten (Cedax) Aztreonam A monobactam None to minimal cross reactivity with other β-lactam agents like penicillin or cephalosporins Similar activity as ceftazidime No gram-positive activity, only gram-neg activity including Pseudomonas aeruginosa Widely distributed Renally eliminated Aztreonam Good safety record Used in place of gent/tobra to avoid their toxicities Uses: Variety of infections - cystitits, pyelo, lower resp tract infns, septicemia, intraabdominal infns, etc. usually with another agent Use monitored Expensive Carbapenems Primaxin (imipenem/cilastatin) MOA: Binds to PBP causing cell death Combined 1:1 with cilastatin (dehydropeptidase inhibitor) to prevent hydrolysis of imipenem Broad spectrum agent: GN, GP, Anaerobes Widely distributed Renally excreted Primaxin Imipenem/Cilastatin Fungal superinfection is a possibility Cross-reactivity with penicillins SE: Seizures (0.4 -1.5%), N, V Monitored antibiotic at WBH Uses: Polymicrobial infections, Resistant organisms Cost: $$ Meropenem/Doripenem Broad spectrum antibiotic similar to Primaxin except it has increased activity against GN organisms Pseudomonas may be susceptible to meropenem/doripenem when it’s resistant to Primaxin (imipenem) Cleared by the kidneys Less epileptogenic (?) Cost:$$ Ertapenem (Invanz) Once daily carbapenem Broad-spectrum agent including anaerobes No activity against Pseudomonas, Enterococcus or Acinetobacter species Given once daily – frequently used as an out-patient drug Side effect profile similar to other carbapenems Cost:$$ Doripenem(Doribax) Newest member of the carbapenems Broad-spectrum antibiotic similar to meropenem FDA approved for cUTI and cIAI…..some may use for HCAP Typically 1 hour infusion (may give over 4 hrs) Less epileptogenic (?) Cost:$$$ Aminoglycosides (amikacin, gentamicin, tobramycin, neomycin, streptomycin) MOA: Binds to bacterial ribosomes and preventing the initiation of protein synthesis causing cell death Very active against GNB including PSA. Active against S. aureus, Enterococci when combined Synergistic with penicillins, nafcillin, vanco Distributes in most fluids and renally eliminated SE: Nephrotoxicity ( when combined with vancomycin), Ototoxicity, Neuromuscular blockade Neuromuscular Blockade Risk is increased in patients receiving NMBA used in anesthesia, hypocalcemia, hypomagnesemia, botulism, myasthenia gravis Can be reversed by administration of IV calcium gluconate Variable response with neostigmine Aminoglycosides Uses: Gram-negative infections either alone or combined…. (usually combined) Gram-positive infections (Viridans strep, Enterococcus, Staphyloccus) when combined with penicillin, nafcillin, vancomycin Can be given as a single daily dose or conventional dosing…dosed on adj body wt in obese patients Need to monitor levels for efficacy and toxicity Polymyxins (Colistin, Polymixin b)) Colistin, a polymyxin antibiotic was first discovered in the 1940s Bactericidal Lack of treatment options for MDR GNB infections has led to re-emergence Active against – Pseudomonas, Acinetobacter, Klebsiella SE: Nephrotoxicity, Neurotoxicity Macrolides Erythromycin, Azithromycin, Clarithromycin MOA - Inhibition of bacterial protein synthesis Bacteriostatic for most part Active against certain gram-positive and gramnegative organisms (S. pneumoniae, Viridans group, N. meningitidis, N. gonorrhoeae, Atypical organisms) Distributed widely SE: GI, thrombophlebitis, QT prolongation Use: Resp Infns (community-acquired), genitourinary, Chlamydial infns, etc Clindamycin MOA: Inhibition of protein synthesis Active against GP organisms and anaerobes Bacteriostatic, bactericidal against some bacteria Widely distributed including bone except in CSF Metabolized by the liver SE: Diarrhea (20%), Pseudomembranous colitis (PMC) due to overgrowth of C. difficile Use: Anaerobic infections, Alternate for Grampositive infns (MRSA, Strep infns, not Enterococci) Clindamycin Use in combination in the treatment of necrotizing streptococcal soft tissue infections (flesh-eating bacteria) Active in presence of high inoculum streptococcal infections Limits toxin production providing increased efficacy Quinolones Agent Norfloxacin Ciprofloxacin Levofloxacin Moxifloxacin Trade Name Noroxin Cipro Levaquin Avelox Quinolones MOA: Inhibits bacterial DNA synthesis causing rapid cell death Bactericidal, Concentration dependent killing Distributes (for most part) into prostate tissue, bile, lung, neutrophils, urine, kidneys, bone, ascitic Excretion - usually kidneys except moxifloxacin (20%) SE: Rash, itching, GI effects, HA, dizziness, Tendon rupture Quinolones Drug Interactions: Seen when coadministered by mouth with aluminium-, magnesium-, sucralfate, iron, MVI w minerals (zinc) Nutritional supplements can reduce BA of FQs NSAIDs - CNS effects Wafarin - PT/INR (monitor) QTc - Antipsychotics, Cisapride, Class IA, Class III antiarrhythmics, ECN, TCAs may prolong QT interval with newer FQs. Quinolones Avoid in patients with hx of convulsions Uses: UTI, Prostatitis, STD, Abdominal Infections, RTIs, Bone and Joint Infns, SSTI, Anthrax, etc Highly abused class of drugs causing an increase in resistance Prolong use may predispose patients to MRSA Tetracyclines (Doxy) MOA: Inhibits protein synthesis Broad spectrum activity Bacteriostatic Widely distributed - Most body fluids Elimination- Biliary SE: GI, CNS, etc Can cause yellow discoloration of teeth in children. Not to be given to kids Use: PID, Chlamydial infns, Mycoplasmas, Rickettsial infns, Lyme dzs, H. Pylori, Anthrax Tigecycline A tetracycline (minocycline) derivative Broad-spectrum activity: Gram-positive including MRSA, Gram-negative (except Pseudomonas, Proteus spp.), anaerobes Large Vd >>> widely distributed in the body AEs- GI (N/V/D) Avoid in kids due to tooth discoloration Biliary excretion Use: CSSI, CIAI Dose: 100 mg x 1, then 50 mg q 12 Vancomycin MOA: Inhibits synthesis of cell wall Bactericidal Activity: Gram-positive aerobes (eg.MRSA) and anaerobes Widely distributed, poor CSF penetration Usual dose: 15 - 20 mg/kg q 12 hours SE: Fever, Chills, Rash, Phlebitis, Nephrotoxicity (rare), Redman syndrome Vancomycin Redman syndrome: Tingling and flushing of the face, neck, and thorax are often experienced, especially if the drug is infused rapidly. This is thought to be related to histamine release secondary to local hyperosmolarity and not to allergic hypersensitivity. Shock has occurred after rapid intravenous infusion of vancomycin, especially during surgery. SLOWDOWN THE INFUSION Vancomycin Use: Treatment of serious gram-positive infections due to -lactam resistant organisms (MRSA, MRSE) Treatment of gram-positive infections in patients with serious allergy to -lactams Oral vancomycin for antibiotic-associated colitis which fails to respond to metronidazole Meningitis, Osteomyelitis, Febrile neutropenia Increased reports of VISA strains Telavancin Bactericidal lipoglycopeptide Mechanism of action Inhibits cell wall synthesis and depolarizes the bacterial cell membrane disrupting its functional integrity Use: Treatment of cSSSI Dose:10 mg/kg administered over 1 hour by IV infusion every 24 hours Cost: $150/750 mg vial 55 Telavancin Most common adverse reactions (≥ 10% of patients) include: taste disturbance, nausea, vomiting, and foamy urine. Serious adverse reactions: nephrotoxicity, infusion-related reactions, and C. difficileassociated diarrhea 56 Dalbavancin & Oritavancin FDA approved 2014 Both these lipoglycopeptide approved for ABSSSI caused by susceptible GP bacteria Dalbavancin – Two-dose regimen: 1000 mg followed one week later by 500 mg x1 Oritavancin –1200 mg x 1 over 3 hrs ADRs: Dalbavancin – N,HA,D Oritavancin – HA, N,V,D, limb and subcutaneous abscesses Coagulation test interference, PT/INR Oxazolidinones Linezolid (Zyvox), Tedizolid (Sivextro) MOA: Inhibition of protein synthesis Bacteriostatic Spectrum of activity - Gram-positive, including Staphylococci, Streptococci, and Enterococci Distribution: Widely distributed, inadequate CSF & bone penetration, limited data so far Metabolism: Liver SE: GI, HA, thrombocytopenia Linezolid (Zyvox), Tedizolid (Sivextro) DI: MAOI, SSRIs (serotonin syndrome), pseudoephedrine ( BP) Serotonin syndrome - Agitation or restlessness confusion, HR, dilated pupils, twitching muscles, sweating, diarrhea, HA, shivering, unconsciousness, etc Bioavailability: IV=PO Use: Tx of resistant gram-positive infections (VRE, MRSA) DI, ADRs may be lower with tedizolid Streptogramins Quinupristin/Dalfopristin (Synercid) MOA: Inhibition of protein synthesis Q/D synergistic together. Slow bactericidal against Enterococcus faecium Not effective against E. faecalis Biliary excretion DI: midazolam, diazepam, CCBs, CSA, PI, etc Rarely used any more Streptogramins Quinupristin/Dalfopristin (Synercid) SE: Muscle and joint pain. Inflammation, pain, and/or phlebitis at injection site PICC line preferred for administration Use: Serious or life-threatening infections associated with VRE-faecium bacteremia and complicated skin and skin structure infections caused by Staph aureus (methicillin susceptible) or Streptococcus pyogenes Daptomycin Cyclic lipopeptide Binds to bacterial cell membranes rapid depolarization inhibition of protein, DNA & RNA synthesis cell death Concentration-dependent Bactericidal Approved for GP bacteremia/endocarditis/SSTI Strictly a Gram-positive agent Reports of non-susceptible strains of MRSA Daptomycin renal elimination…dosage adjustment in renal impairment highly protein bound (~92%) Vd ~ 0.1 L/kg does not penetrate blood-brain barrier no significant drug interactions SE: myopathy – distal extremities (~3% pts) muscle pain, myalgia, tenderness, extremity weakness Nitrofurantoin MOA: Probably inhibits bacterial enzyme though exact mechanism unknown Spectrum: Gram-positive and gram-negative urinary pathogens Urinary concentration Eliminated by kidneys SE: CNS, GI, hepatitis, pulmonary hypersensitivity reactions (cough, chest pain, fever, chills, dyspnea, etc) Rifampin MOA: Impairment of RNA synthesis by inhibiting DNA-dependent RNA polymerase Spectrum: Staphylococci, GPC, Legionella, Mycobacterium tuberculosis, N. meningitidis, etc Very widely distributed Elimination: Biliary Typically used in combination with another abx SE: CNS, GI, Visual changes,etc Rifampin Orange-red discoloration of urine, sweat and permanent staining of soft contact lens can occur DI: A potent inducer reducing levels of many orally administered drugs including midazolam, barbiturates, etc Use: In combination treatment - Mycobacterium infections, Meningitis prophylaxis, Endocarditis, Osteomyelitis, Prosthetic device related, etc Rifaximin Use: Treatment of traveler’s diarrhea caused by noninvasive strains of E. coli & hepatic encephalopathy, C.diff (salvage) MOA: Inhibits bacterial RNA synthesis by binding to bacterial DNA-dependent RNA polymerase Poor absorption SE: Headache,rash, other derm reaxns Fidaxomicin (Dificid) Use: Treatment of diarrhea due to Clostridium difficile MOA: Fidaxomicin is bactericidal against C. difficile by inhibiting RNA polymerase mediated RNA synthesis SE: Dizziness, Rash, Nausea, Vomiting… Compared to oral vancomycin: Non-inferior, lower recurrence rate Cost: $2800/10 day course (20 tablets) Antifungals Polyenes Amphotericin B, Lipid-based amphotericin B Azoles Fluconazole, Itraconazole, Voriconazole Echinocandins Anidulafungin, Caspofungin, Micafungin Other agents - Terbinafine, Flucytosine, Ketoconazole, etc Amphotericin B MOA: Binds to ergosterol in cell membrane, increasing cell permeability causing cell death Spectrum: Most candida species, fusarium species, etc Well distributed into inflamed pleural cavities and joints. Lower in aqueous humor, bronchial secretions, pancreas, bone, etc Elimination: Renal DI: CSA, AG - nephrotoxicity Amphotericin B SE: Nephrotoxicity, Hypokalemia, other electrolyte abnormalities Saline loading may reduce nephrotoxicity associated with amphotericin B Use: Candidiasis, Candiduria, Cryptococcal meningitis (w flucytosine), Aspergillosis, Blastomycosis, Histoplasmosis, Coccidiodomycosis, etc Cost: $ Lipid-Based Amphotericin B Novel approach taken to improve the delivery of ampho B with the main advantage of lower nephrotoxicity. Usual indication is invasive aspergillosis, candidiasis, etc intolerant of ampho B 3 lipid based products available: AmBisome Abelcet Amphotec Lipid-Based amphotericin B Decreased infusion associated side effects Decreased nephrotoxicity but not eliminated Costlier than conventional amphotericin B Ambisome on formulary at WBH Monitored drug Azoles Approved agent for systemic use: Miconazole, Ketoconazole, Fluconazole, Itraconazole, Voriconazole, Posaconazole MOA: Interferes with the synthesis and permeability of fungal cell membranes Activity: Depends on the agent Voriconazole>Itracona>Fluconazol>Ketoconazo Azoles Fluconazole: Broad-spectrum antifungal agent MOA: Inhibits ergosterol synthesis Very widely distributed including CSF DI: phenytoin, CSA, warfarin, etc Elimination: Renal SE: HA, GI, Alopecia, LFTs, Rash Use: Candidiasis, Coccidomycosis, Cryptococcosis, Histoplasmosis, Blastomycosis, etc. Azoles Itraconazole: Broad-spectrum agent MOA: Similar to fluconazole Widely distributed DI: warfarin, benzos, CCBs, CSA, etc Metabolism: Liver SE: GI, HA, Rash, Pruritis CI: Hx of CHF Use:Aspergillosis, Blastomycosis, Cryptococcosis, Coccidioidomycosis, etc Azoles Voriconazole: MOA: Similar to fluconazole Spectrum: Aspergillus, Candida, Fusarium, etc Wide distribution Metabolism: Hepatic SE: Visual disturbances, Fever, Chills, GI, etc DI: CSA, Tacrolimus, Warfarin, Statins, Benzos, CCB, etc Azoles Voriconazole: CI: Quinidine, Sirolimus, Rifampin, LA barbiturates, Rifabutin, Carbamazepine, Ergot alkaloids, Cisapride Avoid IV formulation in renal impairment Use: Invasive aspergillosis, etc. Azoles Posaconazole: MOA – Similar to other azoles Wide distribution Use: Prophylaxis of invasive aspergillus and candida infections…..activity against zygomycetes To be taken with food or supplement Lots of drug-drug interactions Echinocandins Caspofungin: MOA: Inhibits the synthesis of beta-D-glucan, an essential component of the fungal cell wall of aspergillus sp and candida sp Spectrum: Aspergillus species, Candida species Extensively bound to albumin Metabolized by hydrolysis DI: rifampin, efavirenz, phenytoin, DXM, Carbamazepine, CSA Other candins – anidulafungin, micafungin Antiretrovirals 5 classes of drugs NNRTI – efavirenz, nevirapine, etravirine, rilpivirine NRTI – abacavir, didanosline, emtricitabine, lamivudine, stavudine, tenofovir,zidovudine PI – atazanavir, darunavir, fosamprenavir, indinavir, lopinavir + ritonavir, nelfinavir, saquinavir, tipranavir Fusion & entry inhibitors – enfuvirtide, maraviroc Integrase inhibitor – dolutegravir, elvitegravir, raltegravir PK enhancer – cobicistat (no antiretroviral properties) (Always double-check patient’s regimen) (Very important to check for potential drug-drug interactions with drugs that may be used during surgery Surgical Prophylaxis Surgical Care Improvement Project A Medicare Quality Improvement Project CMMS and CDC - Joint development of a new national health care quality improvement project to prevent postoperative infection SCIP core measures have been retired as of January 2015 and the focus will now be on outcomes SURGICAL PROPHYLAXIS Prophylaxis - more common than tx of infn Not all surgeries need prophylaxis Indicated for procedures associated with high infection rates (prosthetic devices) True SSI incidence:post-discharge wound surveillance Important to recognize the difference between prophylaxis and empiric therapy Goals of Surgical Prophylaxis Prevent post-op infection of the surgical site Prevent post-op infectious morbidity and mortality Reduce LOS and cost of hospital care Produce no ADR No effect on the microbial flora of the patient or the hospital Surgical Prophylaxis Ideal Agent Right spectrum of activity High tissue concentration Duration of action Safe Cost Timing of Antibiotic Administration Crucial too early too late Effective tissue concn at the incision time Need the abx to persist the entire duration of surgery Duration of Therapy Shortest effective course Readminister if prolonged or excessive bleeding Readminister if surgery > 3 hours when using cefazolin Surgical Prophylaxis WBH Guidelines Cefazolin for most surgeries except for colorectal, hysterectomies and certain urological procedures Alternates include vancomycin, clindamycin & gentamicin Surgical Prophylaxis KEY POINTS Allergies - obtain and document the reaction Ensure prophylaxis is used when necessary Ensure appropriate cost effective antibiotic is used for prophylaxis Ensure the appropriate time, route and duration of administration and infusion rate for the abx being used for prophylaxis Questions