overview of antimicrobials
DESCRIPTION
OVERVIEW OF ANTIMICROBIALS. Prakash Shah, Pharm.D Clinical Pharmacy Specialist, Infectious Diseases Beaumont Hospital – RO 2012. OBJECTIVES. Understand the differences between various classes of antibacterial agents List various mechanisms of resistance Define Redman syndrome - PowerPoint PPT PresentationTRANSCRIPT
OVERVIEW OF ANTIMICROBIALS
Prakash Shah, Pharm.DClinical Pharmacy Specialist,
Infectious DiseasesBeaumont Hospital – RO
2015
OBJECTIVES
Understand the differences between various classes of antibacterial agents
List various mechanisms of resistanceDefine Redman syndromeGiven a specific antibiotic, list it’s common
side effectDefine the optimum administration time of
antibiotic for surgical prophylaxis
ANTIMICROBIAL ROLE
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 To broaden the spectrum of coverage
intra-abdominal infections (amp/metro/gent) Synergism
Enterococcal endocarditis (penicillin & gentamicin)
Preventing Resistance TB (INH + rifampin)
Disadvantages of combination therapy potential additive nephrotoxicity (gent
+vanco) inactivation - aminoglycosides by PCNS in
renal pts.
PRINCIPLES OF ANTI-INFECTIVE THERAPY
Failure of Antimicrobial Therapy Drug- related: ______________ Host factors
____________________________________________________________________
Microorganisms (related) ______________ ___________________________________
RibosomesNucleus
(Proteins)
2. Penetrate Cell
3. Reach Target and Kill
Organism
Bacterium
Requirements for Antimicrobial Activity
Antibiotics
1. Reach site of infection
Porin Proteins
PBPs
• Decreased Permeability• Drug Efflux• Drug Inactivation• Altered Target
RibosomesNucleus
(Proteins)
Mechanisms of Resistance
Bacterium
Porin Channels(Gram-negatives)
Antibiotics
AntibioticsPorin channels closed or decreased number
Example: Pseudomonas
Beta-lactam Allergy
Allergic reaction- principal toxicity of beta-lactams (pcns, cephalosporins)
Allergic reactions occurs in 7-40/1000 treatment cases
About 1/2 of all allergic reactions occurring in hospitalized patients are attributable to beta-lactams
Antimicrobial Agents
SulfonamidesPenicillinsCephalosporinsAminoglycosidesMacrolidesLincosamidesQuinolonesTetracyclines
GlycylcyclinesGlycopeptidesNitroimidazoleStreptograminsOxazolidinonesNitrofurantoinsMiscellaneous
Sulfonamides and Trimethoprim
TMP/SMX (Bactrim) A synergistic combination, very commonly
usedMOA - generally bactericidal; it acts by
sequential blockade of folic acid enzymes in the synthesis pathway
sulfa TMPPABA----//-------> DHFA-----//---->THFA -- --
FA
Sulfonamides and Trimethoprim
TMP/SMX (Bactrim) Bactericidal when combined o/w
bacteriostaticDosage forms - nearly every route
(topical, ophthalmic, intestinal sulfas, systemic - IV, PO)
Distribution- Widely distributedElimination - RenalSE- N,V,D, hypersensitivity, hematologic,
crystalluriaUse - UTI, CA-MRSA SSTI, PCP,
Stenotrophomonas maltophilia, etc
PENICILLINS
Natural Penicillins (aqueous PCN G, procaine PCN G, Benzathine PCN G and oral PCNs)
MOA - Inhibits PBPs inhibiting bacterial cell wall synthesis
BactericidalDistribution - Widely distributedElimination - mostly renalSE - allergic reaxn, rash, GI, hematologic
PENICILLINS
PENICILLINASE-RESISTANT PENICILLINNafcillin, Oxacillin, Methicillin
DOC- For penicillinase producing S. aureusWidely distributed Metabolism - LiverSE - N,V,D, Hematologic, Hypersensitivity
reaxn (interstitial nephritis)Use - Cellulitis, Osteomyelitis,
Endocarditis, Pneumonia
PENICILLINS
AminopenicillinsAmpicillin, Amoxicillin
DOC for enterococcusDistribution - Widely distributedElimination - RenalSE - GI, hematologic, hypersensitivity
reaxnUse- Endocarditis, Meningitis, Otitis Media,
UTI
PENICILLINS
Antipseudomonal PCNs: carboxypenicillins Ticarcillin (active against serious GNB
including PSA, Enterobacter, Serratia, and Proteus)high sodium content
Antipseudomonal PCNs: Ureidopenicillins Piperacillin (most potent), low sodium content
Piperacillin more potent against PSA vs ticarcillin
PENICILLINS
ß-lactam/ ß-lactamase inhibitor combos
Unasyn (ampicillin/sulbactam) Zosyn (Piperacillin/tazobactam) Timentin (Ticarcillin/Clavulanate)
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/ ß-LACTAMASE INHIBITORS
Timentin = Unasyn = Zosyn for Staphylococci
Timentin/Zosyn>Unasyn for enterobacteriaceae (Citrobacter, Enterobacter, E. coli, Klebsiella, Morganella, Proteus, Salmonella, Serratia, etc)
Pseudomonas… Zosyn > TimentinS. maltophilia… Timentin > ZosynEnterococci… Unasyn > Zosyn > Timentin
CEPHALOSPORINS
An improved spectrum of antibacterial activity, better PK properties, Concentration-independent
MOA: Bactericidal, binds to PBP enzymes preventing cell wall synthesis
Structurally similar to PCN, 1-7% cross reactivity.
Avoid in patients with high grade allergic reactions to PCNs.
Use cautiously in patients with delayed or mild reactions
CEPHALOSPORINS
Based on their spectrum of activity, cephs can be broadly categorized into 5
generationsFirst Generation Cephalosporins -
Cefazolin(Ancef, Kefzol)
Second Generation Cephalosporins - cefuroxime, cefamandole, cefotetan, cefoxitin, cefmetazole
Third Generation Cephalosporins - Cefotaxime, Ceftriaxone, Ceftazidime, Ceftizoxime, Cefobid
Fourth Generation Cephalosporins – Cefepime
Newest – Ceftaroline (Teflaro)
First Generation Cephalosporins
Better activity against gram-positive bacteria and less gram-neg activity
Use: Cellulitis, UTI, Osteo, Surgical prophylaxis
eg. Cefazolin (Kefzol, Ancef)- very well tolerated, longer t1/2 allows less frequent dosing
Cost: $
CEPHALOSPORINS
Second Generation Cephalosporins2 groups within this generation of cephs -
different spectrum of activity & SE profile“true” cephs - cefamandole, cefuroxime -
similar to 1st gen against GPC, MSSA. Incr activity against some GN bacteria
Use: RTI (community acquired), UTIWBH: CefuroximeCost: $
Second Generation Cephalosporins (contd)
Cephamycins - cefoxitin, cefotetan, cefmetazole - Less active against GPC but
better against GN bacteria and active against most anaerobes
Use: Intra-abdominal infns, Surg Prophylaxis,etc
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.
RF - renal, hepatic dzs, poor nutrition, elderly, cancer, wafarin
Third Generation Cephalosporins
Improved activity against hospital acquired gram-neg bacteria including Pseudomonas aeur. (ceftazidime>cefoperazone)
Should be avoided for Enterobacter sp. (may become resistant on therapy)
Less active against staph than 1st & 2nd gen
Highly active against Strep. Pneumoniae(Ceftriaxone & Cefotaxime)
None active against MRSA, Enterococci, etc.
Third Generation Cephalosporins Uses
Cefotaxime: CAP, bacterial meningitis, other infns
Ceftriaxone: CAP, bacterial meningitis, Osteo long t1/2 , biliary elimination, high PB
Ceftazidime: Very active against PSA, poor againstgram-positive. Low protein binding, renally eliminated
Fourth Generation Cephalosporin
CefepimeRapidly crosses the outer membrane of
GNBExcellent 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
Renally excretedSubstituted for aminoglycosides
(gent/tobra) to avoid toxicityDosed twice a day except when treating
Pseudomonas Uses: CAP, HCAP, Febrile neutropenic
patients, Meningitis, Skin and skin structure infections, UTI
Ceftaroline(Teflaro)
Broad-spectrum cephalosporin with GN as well as GP activity including MRSA
FDA approved in Oct 2010Indications: ABSSSI, CABPRestricted to ID onlyUsual dose: 600 mg q 12 hours (IV)
over 1 hour & renal adjustment required
SE: GI, HA, rash
CEPHALOSPORINS
ADVERSE EFFECTS Overall, Cephs have a low incidence of SEThrombophlebitis: 1-5%Hypersensitivity reaxns: Anaphylaxis
(rare) Rash: 1-3% Hematologic reaxns: eosinophilia,
neutropenia, thrombocytosis, hypoprothrombinemia
GI: Diarrhea (2-5%), biliary tract sludge Nephrotoxicity: Rare
CEPHALOSPORINS
ADVERSE EFFECTS Cefamandole, cefotetan, cefoperzone,
moxalactam, cefmetazole have methylthiotetrazole (MTT) side-chain
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
Indications – Comp. UTIs including pyelo and in combn with metronidazole for cIAI
Excellent activity against PSASimilar efficacy when compared to
meropenem for cIAI and levofloxacin for cUTI except in pts with renal impairment
Reduced efficacy in elderly with cIAIUsual dose: 1.5 g q 8 hours
(~$250/day)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 monobactamNone to minimal cross reactivity with
other β-lactam agents like penicillin or
cephalosporinsSimilar activity as ceftazidimeNo gram-positive activity, only gram-neg
activity including Pseudomonas aeruginosa
Widely distributedRenally eliminated
Aztreonam
Good safety recordUsed in place of gent/tobra to avoid their
toxicitiesUses: Variety of infections - cystitits,
pyelo, lower resp tract infns, septicemia, intra-abdominal infns, etc. usually with another agent
Use monitored Expensive
Carbapenems
Primaxin (imipenem/cilastatin)MOA: Binds to PBP causing cell deathCombined 1:1 with cilastatin
(dehydropeptidase inhibitor) to prevent hydrolysis of imipenem
Broad spectrum agent: GN, GP, AnaerobesWidely distributedRenally excreted
PrimaxinImipenem/Cilastatin
Fungal superinfection is a possibilityCross-reactivity with penicillinsSE: Seizures (0.4 -1.5%), N, VMonitored antibiotic at WBHUses: Polymicrobial infections, Resistant
organismsCost: $$
Meropenem/Doripenem
Broad spectrum antibiotic similar to Primaxin except it has increased activity against GN organisms
Pseudomonas may be susceptible to meropenem/doripenem when it’s resistant to Primaxin (imipenem)
Cleared by the kidneysLess epileptogenic (?)Cost:$$
Ertapenem (Invanz)
Once daily carbapenemBroad-spectrum agent including
anaerobesNo activity against Pseudomonas,
Enterococcus or Acinetobacter speciesGiven once daily – frequently used as an
out-patient drug Side effect profile similar to other
carbapenemsCost:$$
Doripenem(Doribax)
Newest member of the carbapenemsBroad-spectrum antibiotic similar to
meropenemFDA approved for cUTI and cIAI…..some
may use for HCAPTypically 1 hour infusion (may give over 4
hrs)Less epileptogenic (?)Cost:$$$
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, vancoDistributes in most fluids and renally
eliminatedSE: 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
BactericidalLack 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 partActive against certain gram-positive and
gram-negative organisms (S. pneumoniae, Viridans group, N. meningitidis, N. gonorrhoeae, Atypical organisms)
Distributed widelySE: GI, thrombophlebitis, QT prolongationUse: Resp Infns (community-acquired),
genitourinary, Chlamydial infns, etc
Clindamycin
MOA: Inhibition of protein synthesisActive against GP organisms and
anaerobesBacteriostatic, bactericidal against some
bacteriaWidely distributed including bone except
in CSFMetabolized by the liverSE: Diarrhea (20%), Pseudomembranous
colitis (PMC) due to overgrowth of C. difficile
Use: Anaerobic infections, Alternate for Gram-positive 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 Trade Name
Norfloxacin Noroxin
Ciprofloxacin Cipro
Levofloxacin Levaquin
Moxifloxacin 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 effectsWafarin - 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 convulsionsUses: 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 synthesisBroad spectrum activityBacteriostaticWidely distributed - Most body fluids Elimination- BiliarySE: GI, CNS, etcCan cause yellow discoloration of teeth in
children. Not to be given to kidsUse: PID, Chlamydial infns, Mycoplasmas,
Rickettsial infns, Lyme dzs, H. Pylori, Anthrax
Tigecycline
A tetracycline (minocycline) derivativeBroad-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 discolorationBiliary excretionUse: CSSI, CIAIDose: 100 mg x 1, then 50 mg q 12
Vancomycin
MOA: Inhibits synthesis of cell wallBactericidalActivity: Gram-positive aerobes (eg.MRSA)
and anaerobesWidely distributed, poor CSF penetrationUsual 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 cSSSIDose: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. difficile-associated diarrhea
56
Dalbavancin & OritavancinFDA 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 hrsADRs: Dalbavancin – N,HA,DOritavancin – HA, N,V,D, limb and
subcutaneous abscessesCoagulation test interference,
PT/INRNot for inpt. use (reimbursement
issues)
OxazolidinonesLinezolid (Zyvox), Tedizolid
(Sivextro)
MOA: Inhibition of protein synthesisBacteriostaticSpectrum of activity - Gram-positive,
including Staphylococci, Streptococci, and Enterococci
Distribution: Widely distributed, inadequate CSF & bone penetration, limited data so far
Metabolism: LiverSE: 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=POUse: Tx of resistant gram-positive
infections (VRE, MRSA)DI, ADRs may be lower with tedizolid
StreptograminsQuinupristin/Dalfopristin (Synercid)
MOA: Inhibition of protein synthesisQ/D synergistic together. Slow
bactericidal against Enterococcus faeciumNot effective against E. faecalisBiliary excretionDI: midazolam, diazepam, CCBs, CSA, PI,
etcRarely used any more
StreptograminsQuinupristin/Dalfopristin (Synercid)
SE: Muscle and joint pain. Inflammation, pain, and/or phlebitis at injection site
PICC line preferred for administrationUse: 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-dependentBactericidalApproved for GP bacteremia/endocarditis/SSTIStrictly a Gram-positive agentReports of non-susceptible strains of MRSA
Daptomycin
renal elimination…dosage adjustment in renal impairment
highly protein bound (~92%)Vd ~ 0.1 L/kgdoes not penetrate blood-brain barrierno significant drug interactionsSE: 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 concentrationEliminated by kidneysSE: 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 distributedElimination: BiliaryTypically used in combination with another
abxSE: 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 absorptionSE: 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 synthesisSE: 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: RenalDI: 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 B3 lipid based products available:
AmBisomeAbelcetAmphotec
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 synthesisVery widely distributed including CSFDI: phenytoin, CSA, warfarin, etcElimination: RenalSE: HA, GI, Alopecia, LFTs, RashUse: Candidiasis, Coccidomycosis,
Cryptococcosis, Histoplasmosis, Blastomycosis, etc.
Azoles
Itraconazole: Broad-spectrum agentMOA: Similar to fluconazoleWidely distributedDI: warfarin, benzos, CCBs, CSA, etcMetabolism: LiverSE: GI, HA, Rash, PruritisCI: Hx of CHFUse:Aspergillosis, Blastomycosis,
Cryptococcosis, Coccidioidomycosis, etc
Azoles
Voriconazole: MOA: Similar to fluconazoleSpectrum: Aspergillus, Candida, Fusarium,
etcWide distributionMetabolism: HepaticSE: Visual disturbances, Fever, Chills, GI,
etcDI: 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 azolesWide distributionUse: 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 albuminMetabolized by hydrolysis DI: rifampin, efavirenz, phenytoin, DXM,
Carbamazepine, CSAOther candins – anidulafungin, micafungin
Antiretrovirals5 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 including midazolam, anesthetics, etc)
Surgical Prophylaxis
Surgical Care Improvement ProjectA 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 infnNot all surgeries need prophylaxisIndicated for procedures associated with
high infection rates (prosthetic devices)True SSI incidence:post-discharge wound
surveillanceImportant 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 careProduce no ADRNo effect on the microbial flora of the
patient or the hospital
Surgical ProphylaxisIdeal Agent
Right spectrum of activityHigh tissue concentration Duration of actionSafeCost
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 ProphylaxisWBH Guidelines
Cefazolin for most surgeries except for colorectal, hysterectomies and certain urological procedures
Alternates include vancomycin, clindamycin & gentamicin
Surgical Prophylaxis
KEY POINTSAllergies - obtain and document the
reaction Ensure prophylaxis is used when
necessaryEnsure appropriate cost effective
antibiotic is used for prophylaxisEnsure the appropriate time, route and
duration of administration and infusion rate for the abx being used for prophylaxis
Questions