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