Download OVERVIEW OF ANTIMICROBIALS

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