Review and Update of Antibacterial Drug Therapy

1
Review and Update of Antibacterial Drug Therapy

• Daniel Streetman, PharmD, MS
• Pharmacotherapy Specialist
• Lexicomp Wolters Kluwer Health

2
Objectives

• Describe factors to consider when prescribing
  antibiotics
• Compare some of the antibiotic classes used to
  treat common infections among community-dwelling
  individuals
• Discuss the clinical application of this
  information for specific types of infections

3
Antimicrobial SelectionSystematic Process

• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor

4
Antimicrobial SelectionSystematic Process

• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor

• Decreased antimicrobial use - particularly of
  broad-spectrum agents
• Less resistance, cost, toxicity

5
Risks of Antimicrobial UseResistance and Toxicity

• Limited pipeline

• CDC "Urgent Threats"
• C. difficile
• Carbapenem-resistant Enterobacteriaceae
• N. gonorrheae

http//www.cdc.gov/drugresistance/threat-report-20
13/pdf/ar-threats-2013-508.pdf Cochrane Database
Syst Rev 2013 Jan 31.
6
Risks of Antimicrobial UseResistance and Toxicity

• Review of 11 RCTs, gt3500 AOM episodes
• Per 100 abx tx's
• 5 fewer w/ pain at 2-3 d
• 3 fewer perforations
• 9 fewer infx of o/ear
• no diff in other outcomes
• no diff in future AOM risk
• 7 toxicities (V/D, rash)

• CDC "Urgent Threats"
• C. difficile
• Carbapenem-resistant Enterobacteriaceae
• N. gonorrheae

http//www.cdc.gov/drugresistance/threat-report-20
13/pdf/ar-threats-2013-508.pdf Cochrane Database
Syst Rev 2013 Jan 31.
7
Antibiotics Are Common Cause of ADE-Related ER
Visits
Clin Infect Dis 200847735-43.
8
Antimicrobial SelectionSystematic Process

• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor

9
Confirm Infection and Identify Pathogen

• Fever, Leukocytosis, Local signs/symptoms
• Drug-induced fever
• Antipyretic use
• Steroid-induced leukocytosis
• Viral vs. Bacterial vs. Other
• Sample infected tissue (Gm-stain, culture, etc.)
• Contamination vs. Infection
• Suspected pathogen(s) for specific site

10
Pharyngitis Viruses S.pyogenes
Acute Otitis Media S.pneumoniae H.influenzae
M.catarrhalis Viruses
CABP S.pneumoniae H.influenzae M.catarrhalis
M.pneumoniae C.pneumoniae L.pneumophila Viruses
UTI E.coli (85)
S.saprophyticus Enterococcus spp. K.pneumoniae
P.aeruginosa Proteus spp. Enterobacter spp.
Aspiration Pneumonia Oral anaerobes
S.viridans Enteric gm(-) bacilli
SSTI S .aureus S.pyogenes
S.agalactiae
Hospital-Acquired S.aureus (MRSA) ESBL gm(-)s
11
Antimicrobial SelectionSystematic Process

• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor

12
Initiate Presumptive Therapy

• ß-lactams
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactams
• Macrolides
• Tetracyclines
• Fluoroquinolones
• Sulfonamides
• Aminoglycosides

• Vancomycin
• Clindamycin
• Metronidazole
• Linezolid
• Quinupristin/Dalfopristin
• Daptomycin
• Telavancin
• Rifamycins
• Urinary antiseptics

13
Initiate Presumptive TherapyPatient Factors

• Severity and acuity
• Allergies
• Age
• Comorbidities (including pregnancy)
• Genetics
• Concurrent medications

14
Initiate Presumptive TherapyAllergy

• Is this rash an allergy?
• "Ampicillin rash"
• up to 80-100 of pts with mononucleosis
• 33 of amoxicillin recipients vs. 23 non-amox
• cefalexin, cefaclor, cefadroxil most closely
  related
• 72 tolerated these vs. 97 of other
  cephalosporins
• Post-viral rash
• Streptococcal rash

Pediatrics 2013131(5)e1424-7. J Antimicrob
Chemother 200760(1)107-11.
15
Initiate Presumptive TherapyAllergy

• 80-90 of those with reported allergy to PCN have
  negative skin test
• 97-99 can receive PCN without immediate-type
  hypersensitivity reaction

Mayo Clin Proc 200580405-10. N Engl J Med
2001345804-9.
16
Monitoring Renal Function for Drug Therapy

• Glomerular filtration is likely the most
  sensitive to age-related change (vs. secretion or
  reabsorption)
• Est Creatinine Clearance
• 140-age(yrs) ? Weight (kg) (Serum Creatinine ?
  72)
• ltNote multiply above result by 0.85 for
  females!gt
• This often overestimates GFR in older patients!

Renal blood flow ?s from 120 mL/min at 30-40
years of age to 60 mL/min at 80 years of age.
17
Initiate Presumptive TherapyAge

• Caution in older pts
• ß-lactams, vanco, etc.
• Fluoroquinolones
• Isoniazid

• Caution in children
• Tetracyclines
• Chloramphenicol

Incidence of INH Hepatotoxicity
18
Initiate Presumptive TherapyComorbidities

• Renal, hepatic disease
• Cystic fibrosis, Diabetes, Burn patients,
  Neutropenic patients, HIV/AIDS, etc.
• Specific toxicity-related concerns
• Ticarcillin, piperacillin high Na content
• Sulfonamides crystalluria
• Fluoroquinolones myasthenia gravis

19
Initiate Presumptive TherapyConcurrent
Medications

• Macrolides inhibit CYP3A4
• Fluoroquinolones inhibit CYP1A2 binding to
  Al3, Mg3, Ca2, Fe3
• Tetracyclines binding Al3, Mg3, Ca2, Fe3
• Linezolid MAO inhibition
• ß-lactams increased conc's with probenecid
• Rifampin major enzyme inducer

20
Initiate Presumptive TherapyDrug Factors

• Local sensitivities/recommendations
• Pharmacodynamics
• Pharmacokinetics
• Route
• Distribution
• Interactions
• Toxicities
• Cost

21
AntibioticsLocal Sensitivities and
Recommendations

• SST treat for 7-10 days (PO) or 10-14 days
  (IV/PO)
• If CA-MRSA is not a concern dicloxacillin or
  cephalexin
• If CA-MRSA is concern clindamycin, doxycycline,
  or SMZ/TMP ( dicloxacillin or cephalexin)

Concern for MRSA increases with Abscesses,
Exudative lesions, Community prevalence of gt 15
22
Initiate Presumptive TherapyPharmacodynamics -
Mechanism(s) of Action

• Most abx work by only few general mechanisms
• Disrupt bacterial cell wall
• Beta-lactams, Vancomycin
• Interfere with bacterial protein/DNA/RNA
  synthesis
• Macrolides/Azalides/Ketolides, Tetracyclines,
  Aminoglycosides, Clindamycin, Linezolid,
  Quinupristin/Dalfopristin
• Block bacterial folic acid synthesis
• Sulfonamides, Trimethoprim
• Disrupt DNA transcription/translation
• Fluoroquinolones
• Other
• Daptomycin, Metronidazole, most anti-TB drugs

23
Initiate Presumptive TherapyPharmacodynamics -
"cidal" vs. "static"

• Antibacterials that actually kill the bacteria in
  the body are classified as "bactericidal"
• kill at least 99.9 of bacterial population
• less than 3-log reduction "bacteriostatic"
• Most drugs that inhibit protein synthesis are
  only bacteriostatic (exception aminoglycosides)
• Other "cidal" drugs include beta-lactams,
  vancomycin, fluoroquinolones

24
Initiate Presumptive TherapyPharmacodynamics -
Optimal dosing

• Beta-lactams
• Time gt MIC
• Aminoglycosides
• PeakMIC
• Fluoroquinolones

25
Initiate Presumptive TherapyPharmacokinetics

• Route of administration
• Low/no oral bioavailability
• Vancomycin, Rifaximin, Fidaxomicin
• High/consistent oral bioavailability
• Fluoroquinolones, Linezolid
• Distribution
• Macrolides, Fluoroquinolones, Tetracyclines with
  activity vs. Mycoplasma pneumoniae, Legionella
  pneumophila, Chlamydia pneumoniae

26
Initiate Presumptive TherapyDrug Factors

• Local sensitivities/recommendations
• Pharmacodynamics
• Pharmacokinetics
• Route
• Distribution
• Interactions
• Toxicities
• Cost

27
Antimicrobial SelectionSystematic Process

• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor

28
Monitor Therapy

• Fever, WBC, Local signs and symptoms
• Need for changing therapy
• Failure
• Streamlining, IV to PO
• Antimicrobial serum concentrations
• Toxicity-related testing

29
Monitor TherapyRecommended Testing

• Antimicrobial serum concentrations
• Aminoglycosides
• Vancomycin
• Chloramphenicol
• Toxicity-related testing
• Renal function, hydration status

30
Monitor TherapyFailure

• Inadequate diagnosis
• Poor initial drug selection
• Poor source control
• New infection
• Resistant population
• Secondary infection

31
Supplemental Information and Case Discussions
32
CABPPathogens and Guidelines

• Likely pathogens
• S. pneumoniae, H. influenzae, M. catarrhalis,
  M. pneumoniae, C. pneumoniae, L.
  pneumophila, viruses
• CABP macrolide, doxycycline, respiratory
  quinolone, or ß-lactammacrolide
• 5 days, depending on clinical picture
• 5 days azithromycin or levofloxacin (750 mg
  dose)
• 7-10 days other oral agents
• Only if bacterial ... 20-25 of abx use
  'inappropriate'

33
Macrolides

• Erythromycin, Azithromycin (Zithromax),
  Dirithromycin (Dynabac), Clarithromycin (Biaxin)
• Inhibit protein synthesis
• Bind to 50S ribosomal subunit
• Usually bacteriostatic, but can be bactericidal
• Spectrum Gram (staph, strep) Atypicals
  (Mycoplasma, Chlamydia, Legionella)
• Substrates and inhibitors of CYP3A4, Pgp
• Azithromycin has unique kinetics

34
Macrolides

• Abdominal pain, N/V/D
• QTc prolongation
• May increase GI motility ... motilin agonist
• specific to erythromycin and azithromycin

35
Macrolide Drug Interaction Concerns

• Moderate to Strong CYP3A4 inhibitors
• Steroids, CCBs, statins, BZDs, AEDs, more
• Inhibit OATP1B1
• Increase pravastatin AUC 2.1-fold, other statins
  by up to 12-fold
• Inhibit P-glycoprotein
• P-glycoprotein, newer anticoagulants

36
Macrolides May Increase Risk of Cardiac-Related
Death

• Erythromycin known to prolong QT interval
• Also inhibitor of CYP3A, OATP1B1, and
  p-glycoprotein
• gt2-fold increase in SCD with eryth vs. o/abx
• gt5-fold increase with eryth and CYP3A inhibitor
• Clarithromycin also seems to share similar risks
  (QT effects, CYP3A, p-gp, etc.)

N Engl J Med 20043511089-96. BMJ
2013346f1235.
37
Does Azithromycin Increase Risk of
Cardiac-Related Deaths?
N Engl J Med 20133681704-12. N Engl J Med
20123661881-90.
38
Tetracyclines

• Tetracycline, doxycycline (Vibramycin),
  minocycline (Minocin), tigecycline (Tygacil)
• Inhibit protein synthesis
• Inhibit 30S ribosomal subunit ... bacteriostatic
• Broad spectrum agents, including atypicals,
  H.pylori, Propionibacterium acnes
• Including MRSA
• Variable lipid solubility and half-life (6 to gt24
  hrs)
• TCN 6-8 hrs
• minocycline, doxycycline, tigecycline 16 hrs

39
Tetracyclines

• Interactions divalent chelation (GI
  interactions)
• GI burning, cramps, N/V/D
• Tooth discoloration, suppressed long bone growth
• Avoid in later pregnancy and in children lt 8 yrs
  of age
• Photosensitivity, hepatotoxicity
• Special caution with expired meds

40
Interactions with Tetracyclines and
Fluoroquinolones

• 84 ? in doxycycline AUC with Al3/Mg3-based
  antacid
• 51 ? in doxy and TCN absorption with bismuth
• FQs also inhibit CYP1A2

? 45-97 with Al3/Mg3
? 3-63 with Ca2
41
Fluoroquinolones

• Ciprofloxacin (Cipro), Levofloxacin (Levaquin),
  Norfloxacin (Noroxin), Ofloxacin (Floxin),
  Lomefloxacin (Maxaquin), Sparfloxacin (Zagam),
  Moxifloxacin (Avelox), Gemifloxacin (Factive)
• Inhibits DNA gyrase (topoisomerase II) and
  toposiomerase IV required for DNA uncoiling
  during replication and cell division
• Bactericidal
• Active against many Gm(-) aerobes many have good
  activity vs. many Gm() aerobes

42
Fluoroquinolones

• By 'generation'
• 1st nalidixic acid
• 2nd Ciprofloxacin (Cipro), Levofloxacin
  (Levaquin), Norfloxacin (Noroxin), Ofloxacin
  (Floxin)
• 3rd Gemifloxacin (Factive)
• 4th Moxifloxacin (Avelox)
• "Respiratory" or not
• "Respiratory" quinolone levofloxacin,
  moxifloxacin, gemifloxacin
• Ophthalmic gatifloxacin, besifloxacin,
  ciprofloxacin, levofloxacin, moxifloxacin,
  ofloxacin

43
Fluoroquinolones

• Nearly 100 bioavailable (chelation issues)
  hepatic metabolism, renal excretion
• Resistance altered binding target and/or efflux
  mechanisms (high- vs. low-level) low frequency
• Increased use frequently cause, thus need to
  restrict
• Animal feed
• Polyvalent cations, CYP1A2 substrates
• GI effects, QTc prolongation, hyper/hypoglycemia,
  arthropathy and tendonitis (limits pediatric
  use), seizures

44
Fluoroquinolone Toxicities

• Neuropsychiatric effects
• CNS stimulation
• Tendon rupture
• Age gt 60 yrs
• Steroid use
• Post-transplant
• QT prolongation
• Hyper-/hypoglycemia

45
AOMPathogens and Guidelines

• S. pneumoniae, H. influenzae, M. catarrhalis,
  viruses
• OM amoxicillin (or amox/clavulanic acid or
  clindamycin or cephalosporin)
• Cephalosporins cefuroxime, cefpodoxime,
  cefdinir, ceftriaxone (IV/IM)
• Alternatives macrolide, sulfamethoxazole/trimeth
  oprim
• lt 2 yrs old 10 days
• lt 6 yrs old 7-10 days
• gt 6 yrs old 5-7 days
• Only recommended if bilateral, severe
  presentation, or failure to improve after 48-72
  hrs of "watchful waiting"

46
PharyngitisPathogens and Guidelines

• Viral, S. pyogenes (20-30 kids, 5-15 adults)
• Pharyngitis PCN VK, amoxicillin, or
  cephalosporin (or clindamycin)
• 10 days
• Only if Strep-positive ... otherwise, likely
  viral
• Amoxicillin higher-dose, given once daily is
  becoming preferred dose
• Treatment decreases infectious period from 10
  days to approx 24 hrs, and decreases symptoms by
  1-2 days

47
Beta-LactamsPenicillins

• Block cross-linking of bacterial cell wall by
  endopeptidases (PBPs)
• on interior of cell wall
• Time-dependent killing
• Resistance
• Beta-lactamases (H.flu)
• Alteration of PBPs (MRSA)

48
Beta-LactamsPenicillin Classes

• Natural penicillins
• Penicillin
• Extended-spectrum
• Ampicillin, amoxicillin
• Antistaphylococcal penicillins (ß-lac resistant)
• Methicillin, nafcillin, oxacillin, dicloxacillin
• Antipseudomonal penicillins
• Piperacillin, ticarcillin

49
PenicillinsNotable Penicillins

• Amoxicillin vs. Ampicillin
• Amoxicillin/Clavulanic acid (Augmentin)
• Ampicillin/Sulbactam (Unasyn)
• May cause non-allergic rash
• Piperacillin vs. Ticarcillin
• Piperacillin/Tazobactam (Zosyn)
• Ticarcillin/Sulbactam (Timentin)
• HIGH sodium content

50
Beta-LactamsCephalosporins

• Block cross-linking of bacterial cell wall by
  endopeptidases (PBPs)
• on interior of cell wall
• Resistance
• Beta-lactamases
• Alteration of PBPs

51
Beta-LactamsCephalosporins

• Organized into "generations" based on spectrum
  and year introduced
• Generally, with each generation
• Increased gm(-) and anaerobic activity
• Greater resistance to ?-lactamase
• Increased penetration of CNS
• Mostly renally eliminated
• Ceftriaxone has hepatic/biliary elimination

52
Beta-LactamsCephalosporins

• First Generation
• cefazolin, cephalexin, cefadroxil
• Second Generation
• cefuroxime, cefoxitin, cefotetan, cefprozil,
  cefaclor
• Third Generation
• ceftazidime, ceftriaxone, cefotaxime,
  cefixime, ceftibuten, cefdinir, cefditoren,
  cefpodoxime
• Fourth Generation cefepime
• Fifth Generation ceftaroline

Available as injectable product (IV and/or IM)
53
Amoxicillin in AOM

• 80-90 mg/kg/day dosing is preferred over
  conventional 40-45 mg/kg/day
• Effective vs. PRSP
• Alternatives only for treatment failure or
  allergy
• Amoxicillin/clavulanate (prefer 141 ratio)
• Cephalosporins
• Macrolide, Clindamycin, SMZ/TMP

54
Cost ComparisonPharyngitis Treatment Options
55
UTI

• UTI (lower) SMZ/TMP, nitrofurantoin, quinolone
• Uncomplicated
• SMZ/TMP or FQ 3 days
• nitrofurantoin 5 days
• amoxicillin/clavulanate 3 days
• Complicated
• SMZ/TMP or FQ 7-10 days
• amoxicillin/clavulanate 7-10 days
• UTI (upper) SMZ/TMP, ciproflox, levoflox
• SMZ/TMP 14 days
• ciprofloxacin 7-14 days
• levofloxacin 5-14 days

56
SSTIPathogens and Guidelines

• S. aureus, S. pyogenes, S. agalactiae
• SST treat for 7-10 days (PO) or 10-14 days
  (IV/PO)
• If CA-MRSA is not a concern dicloxacillin or
  cephalexin
• If CA-MRSA is concern clindamycin, doxycycline,
  or SMZ/TMP ( dicloxacillin or cephalexin)

57
Other Unique Antibacterials

• Telithromycin (Ketek)
• Related to macrolides reserve for MDRSP
• Serious liver toxicity risks drug interaction
  risk
• Linezolid (Zyvox)
• Active vs. VRE, MRSA
• Weak MAO inhibition interaction risks!
• Quinupristin/Dalfopristin (Synercid)
• Active vs. VRE, MRSA, MRSE, MDRSP
• Hepatotoxicity, phlebitis/local pain,
  arthralgia/myalgia
• Daptomycin (Cubicin)
• Unique MOA (depolarizes cell membrane)
• Active vs. MRSA
• Myopathy, neuropathy

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59
AntibioticsGuidelines for Common Infections

• CABP macrolide, doxycycline, respiratory
  quinolone, or ß-lactammacrolide
• 5 days, depending on clinical picture
• Only if bacterial ... 20-25 of abx use
  'inappropriate'
• OM amoxicillin (or amox/clavulanic acid or
  clindamycin or cephalosporin)
• lt 2 yrs old 10 days
• lt 6 yrs old 7-10 days
• gt 6 yrs old 5-7 days
• Only recommended if bilateral, severe
  presentation, or failure to improve after 48-72
  hrs of "watchful waiting"

60
AntibioticsGuidelines for Common Infections

• Pharyngitis PCN VK, amoxicillin, or
  cephalosporin (or clindamycin)
• 10 days
• Only if Strep-positive ... otherwise, likely
  viral
• SST treat for 7-10 days (PO) or 10-14 days
  (IV/PO)
• If CA-MRSA is not a concern dicloxacillin or
  cephalexin
• If CA-MRSA is concern clindamycin, doxycycline,
  or SMZ/TMP ( dicloxacillin or cephalexin)
• UTI SMZ/TMP, nitrofurantoin, quinolone
• SMZ/TMP or FQ 3 days
• nitrofurantoin 5 days

61
Spectrum of Activity

• Drugs vary widely regarding spectrum of activity,
  and detailed knowledge of this will require much
  study and/or experience
• Even within same class, spectrum can be quite
  different
• A few general notes about spectrum for each group
  of drugs follows in class-specific discussions ...

62
Methods of Resistance

• Inactivating enzymes
• ?-lactamase, etc.
• Alteration of drug target
• Changes in 50S, 30S subunits
• Mutation in DNA gyrase
• Altered penicillin binding proteins
• Expression of drug efflux transporter
• TCNs, macrolides, fluoroquinolones

63
More About Resistance

• Transferrable
• Person-to-person
• Bacteria-to-bacteria
• Plasmid-to-plasmid
  plasmid-to-chromosome
• Strongly influenced by antibiotic use
• Lower concentrations
• Incomplete courses
• Increasingly limited antibiotic pipeline
• Most current abx discovered pre-1970

64
Antibiotics
65
CephalosporinsAdverse Effects

• Allergy - cross reaction up to 10 w/PCN
• 1-2 w/o PCN allergy
• CNS - drug fever, seizures
• Hematologic
• Hemolytic anemia, rare bone marrow suppression
• N-methylthiotetrazole (NMTT) side chain
  interferes with vitamin-K dependent coagulation
  factor synthesis possible disulfiram reaction
  ... cefotetan
• Diarrhea and C.difficile colitis
• Interstitial nephritis

66
Beta-LactamsCarbapenems, Monobactams

• Imipenem, meropenem, ertapenem, doripenem
• Severe polymicrobial infections, very broad
  spectrum
• Cross-reactive with penicillins/cephalosporins
• Cilastatin dipeptidase inhibitor (used
  w/imipenem)
• Seizure risk
• Aztreonam
• Limited to gram negative rods
• May include Pseudomonas
• Occasionally used as alternative to AG
• No cross-allergy to PCNs
• Concern with ceftazidime

67
Vancomycin

• Inhibits bacterial peptidoglycan production
• Binds D-ala-D-ala component of peptidoglycan
• Only effective vs. gm() organisms
• Critical "last resort" medication
• Emerging resistance a concern
• Kinetics
• No oral absorption
• 90 renal elimination
• Phlebitis, Red Man syndrome, nephrotoxicity,
  ototoxicity

68
Aminoglycosides

• Gentamicin, tobramycin, amikacin
• Inhibition of protein synthesis, altered protein
  synthesis (due to misreading)
• binds to 30S ribosomal subunit
• bactericidal (concentration-dependent)
• Spectrum mostly aerobic Gm(-)
• Syngery with ß-lactams (conc.-dependent
  instability)
• Renal excretion
• Highly variable elimination
• Can use serum concentrations to guide dosing

69
Aminoglycosides

• Nephrotoxicity
• High trough concentrations (Cmin gt 2)
• Cumulative exposure, elderly, other nephrotoxic
  drugs
• Ototoxicity, neuromuscular blockade (high dose)

70
Sulfonamides

• Sulfamethoxazole, others
• Inhibits bacterial folic acid synthesis
• p-aminobenzoic acid (PABA) analog that competes
  as substrate for folic acid synthesis (required
  for DNA synthesis)
• Often given with trimethoprim (inhibitor of folic
  acid activation) to achieve synergy
• Broad spectrum (including MRSA)
• Pneumocystis jiroveci (P. carinii)

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Sulfonamides

• Hepatic metabolism (acetylation), mostly renal
  excretion
• Interactions warfarin, sulfonylureas
• ADRs allergy (cross-sensitive to other sulfas)
• Can precipitate in acidic urine (drink water)
• Hemolytic anemia (G6PD)
• Photosensitivity
• Severe skin reactions (SJS, TENs)
• Megaloblastic anemia (rare)

72
Other Unique Antibacterials

• Telithromycin (Ketek)
• Related to macrolides reserve for MDRSP
• Serious liver toxicity risks drug interaction
  risk
• Linezolid (Zyvox)
• Active vs. VRE, MRSA
• Weak MAO inhibition interaction risks!
• Quinupristin/Dalfopristin (Synercid)
• Active vs. VRE, MRSA, MRSE, MDRSP
• Hepatotoxicity, phlebitis/local pain,
  arthralgia/myalgia
• Daptomycin (Cubicin)
• Unique MOA (depolarizes cell membrane)
• Active vs. MRSA
• Myopathy, neuropathy

73
Clindamycin (Cleocin)

• Inhibits protein synthesis (binds 50S)
• Spectrum most anaerobes (except C. difficile),
  Gm() aerobes
• Active against MRSA
• Widely distributed (except CNS)
• Largely metabolized, mixed elimination
• Diarrhea, pseudomembranous colitis
• Hepatotoxicity, rashes, blood dyscrasias

74
Metronidazole (Flagyl)

• Classified as antiprotozoal
• Spectrum anaerobes including Bacteroides and
  Clostridium
• MOA
• Accepts electrons (deprives fermentation
  chemistry)
• Reduced molecule toxic to DNA
• Mixed anaerobic and colitis (GI), also CNS
  (abscess)
• ADR disulfiram effect

75
Rifaximin (Xifaxan)

• Rifamycin antibiotic indicated for (1) travelers
  diarrhea due to E. coli and (2) hepatic
  encephalopathy
• Use for C. difficile-associated diarrhea (CDAD)
  is an unlabeled use (treatment, "chaser")
• Inhibits RNA synthesis
• 200mg and 550mg tablets given BID-TID
• Limited systemic absorption
• Low side effect, interaction potential

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Fidaxomicin (Dificid)

• Macrolide antibiotic indicated for treatment of
  C. difficile-associated diarrhea
• Inhibits RNA synthesis (bactericidal)
• Available as 200 mg tablets, given BID
• Minimal systemic absorption (lt10) in healthy
  volunteers
• Appears to be higher (2- to 6-fold) in patients

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