Transcript Antibiotic Update

Review and Update of
Antibacterial Drug Therapy
Daniel Streetman, PharmD, MS
Pharmacotherapy Specialist
Lexicomp | Wolters Kluwer Health
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
Antimicrobial Selection
Systematic Process
• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor
Antimicrobial Selection
Systematic Process
• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor
• Decreased antimicrobial use particularly of broad-spectrum agents
• Less resistance, cost, toxicity
Risks of Antimicrobial Use
Resistance and Toxicity
• Limited pipeline
• CDC "Urgent Threats"
– C. difficile
– Carbapenem-resistant
Enterobacteriaceae
– N. gonorrheae
http://www.cdc.gov/drugresistance/threatreport-2013/pdf/ar-threats-2013-508.pdf
Cochrane Database Syst Rev 2013 Jan 31.
Risks of Antimicrobial Use
Resistance and Toxicity
• Review of 11 RCTs,
>3500 AOM episodes
• Per 100 abx tx's:
• CDC "Urgent Threats"
– C. difficile
– Carbapenem-resistant
Enterobacteriaceae
– N. gonorrheae
–
–
–
–
–
–
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)
http://www.cdc.gov/drugresistance/threatreport-2013/pdf/ar-threats-2013-508.pdf
Cochrane Database Syst Rev 2013 Jan 31.
Antibiotics Are Common Cause
of ADE-Related ER Visits
Clin Infect Dis 2008;47:735-43.
Antimicrobial Selection
Systematic Process
• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor
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
Acute Otitis Media:
S.pneumoniae
H.influenzae
M.catarrhalis
Viruses
UTI:
E.coli (85%)
S.saprophyticus
Enterococcus spp.
K.pneumoniae
P.aeruginosa
Proteus spp.
Enterobacter spp.
SSTI:
S .aureus
S.pyogenes
S.agalactiae
Pharyngitis:
Viruses
S.pyogenes
CABP:
S.pneumoniae
H.influenzae
M.catarrhalis
M.pneumoniae
C.pneumoniae
L.pneumophila
Viruses
Aspiration
Pneumonia:
Oral anaerobes
S.viridans
Enteric gm(-) bacilli
Hospital-Acquired:
S.aureus (MRSA)
ESBL gm(-)s
Antimicrobial Selection
Systematic Process
• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor
Initiate Presumptive Therapy
• β-lactams
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Penicillins
Cephalosporins
Carbapenems
Monobactams
Macrolides
Tetracyclines
Fluoroquinolones
Sulfonamides
Aminoglycosides
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•
•
•
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Vancomycin
Clindamycin
Metronidazole
Linezolid
Quinupristin/Dalfopristin
Daptomycin
Telavancin
Rifamycins
Urinary antiseptics
Initiate Presumptive Therapy
Patient Factors
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Severity and acuity
Allergies
Age
Comorbidities (including pregnancy)
Genetics
Concurrent medications
Initiate Presumptive Therapy
Allergy
• 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 2013;131(5):e1424-7. J Antimicrob Chemother 2007;60(1):107-11.
Initiate Presumptive Therapy
Allergy
• 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 2005;80:405-10. N Engl J Med 2001;345:804-9.
Monitoring Renal Function for
Drug Therapy
• Est Creatinine Clearance =
[140-age(yrs)]  Weight (kg)
(Serum Creatinine  72)
<Note: multiply above result
by 0.85 for females!>
• This often overestimates
GFR in older patients!
Creatinine Clearance (mL/min)
• Glomerular filtration is likely
the most sensitive to agerelated change (vs.
secretion or reabsorption)
140
120
100
80
60
40
20
Renal blood flow s from 120
mL/min at 30-40 years of age to
60 mL/min at 80 years of age.
0
30s 40s 50s 60s 70s 80s
Age (Decade)
Initiate Presumptive Therapy
Age
Caution in children:
• Tetracyclines
• Chloramphenicol
Caution in older pts:
• β-lactams, vanco, etc.
• Fluoroquinolones
• Isoniazid
Incidence (%)
Tetracycline tooth staining
9
8
7
6
5
4
3
2
1
0
21-35
35-49
50-64
65+
Patient Age (yrs)
Incidence of INH Hepatotoxicity
Initiate Presumptive Therapy
Comorbidities
• 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
Initiate Presumptive Therapy
Concurrent Medications
• Macrolides: inhibit CYP3A4
• Fluoroquinolones: inhibit CYP1A2; binding
to Al3+, Mg3+, Ca2+, Fe3+
• Tetracyclines: binding Al3+, Mg3+, Ca2+, Fe3+
• Linezolid: MAO inhibition
• β-lactams: increased conc's with probenecid
• Rifampin: major enzyme inducer
Initiate Presumptive Therapy
Drug Factors
• Local sensitivities/recommendations
• Pharmacodynamics
• Pharmacokinetics
– Route
– Distribution
– Interactions
• Toxicities
• Cost
Antibiotics
Local 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 > 15%
Initiate Presumptive Therapy
Pharmacodynamics - 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
Initiate Presumptive Therapy
Pharmacodynamics - "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
Initiate Presumptive Therapy
Pharmacodynamics - Optimal dosing
• Beta-lactams
– Time > MIC
• Aminoglycosides
– Peak:MIC
• Fluoroquinolones
Initiate Presumptive Therapy
Pharmacokinetics
• 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
Initiate Presumptive Therapy
Drug Factors
• Local sensitivities/recommendations
• Pharmacodynamics
• Pharmacokinetics
– Route
– Distribution
– Interactions
• Toxicities
• Cost
Antimicrobial Selection
Systematic Process
• Confirm infection
• Identify pathogen(s)
• Begin presumptive therapy
• Monitor
Monitor Therapy
• Fever, WBC, Local signs and symptoms
• Need for changing therapy
– Failure
– Streamlining, IV to PO
• Antimicrobial serum concentrations
• Toxicity-related testing
Monitor Therapy
Recommended Testing
• Antimicrobial serum concentrations
– Aminoglycosides
– Vancomycin
– Chloramphenicol
• Toxicity-related testing
– Renal function, hydration status
Monitor Therapy
Failure
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Inadequate diagnosis
Poor initial drug selection
Poor source control
New infection
– Resistant population
– Secondary infection
Supplemental Information
and Case Discussions
CABP
Pathogens and Guidelines
• Likely pathogens:
– S. pneumoniae, H. influenzae, M. catarrhalis,
M. pneumoniae, C. pneumoniae, L. pneumophila,
viruses
• CABP: macrolide, doxycycline, respiratory
quinolone, or β-lactam+macrolide*
– ≥ 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'
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
Macrolides
• Abdominal pain, N/V/D
• QTc prolongation
• May increase GI motility ... motilin agonist
– specific to erythromycin and azithromycin
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
Macrolides May Increase Risk
of Cardiac-Related Death
• Erythromycin known to prolong QT interval
– Also inhibitor of CYP3A, OATP1B1, and
p-glycoprotein
– >2-fold increase in SCD with eryth vs. o/abx
– >5-fold increase with eryth and CYP3A inhibitor
• Clarithromycin also seems to share similar
risks (QT effects, CYP3A, p-gp, etc.)
N Engl J Med 2004;351:1089-96. BMJ 2013;346:f1235.
Does Azithromycin Increase
Risk of Cardiac-Related Deaths?
N Engl J Med 2013;368:1704-12. N Engl J Med 2012;366:1881-90.
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 >24 hrs)
– TCN = 6-8 hrs
– minocycline, doxycycline, tigecycline = ≥ 16 hrs
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 < 8 yrs of age
• Photosensitivity, hepatotoxicity
– Special caution with expired meds
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
Bioavailability (%)
Al3+/Mg3+
Ca2+
100
90
80
70
60
50
40
30
20
10
0
ciproflox levoflox norflox
 45-97% with Al3+/Mg3+
 3-63% with Ca2+
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
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
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
Fluoroquinolone Toxicities
• Neuropsychiatric
effects
– CNS stimulation
• Tendon rupture
– Age > 60 yrs
– Steroid use
– Post-transplant
• QT prolongation
• Hyper-/hypoglycemia
AOM
Pathogens 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/trimethoprim
– < 2 yrs old = 10 days
– < 6 yrs old = 7-10 days
– > 6 yrs old = 5-7 days
**Only recommended if bilateral, severe presentation, or
failure to improve after 48-72 hrs of "watchful waiting"
Pharyngitis
Pathogens 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
Beta-Lactams
Penicillins
• 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)
Beta-Lactams
Penicillin “Classes”
• Natural penicillins
– Penicillin
• Extended-spectrum
– Ampicillin, amoxicillin
• Antistaphylococcal penicillins (ß-lac resistant)
– Methicillin, nafcillin, oxacillin, dicloxacillin
• Antipseudomonal penicillins
– Piperacillin, ticarcillin
Penicillins
Notable 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
Beta-Lactams
Cephalosporins
• Block cross-linking of bacterial cell wall
by endopeptidases (“PBPs”)
– on interior of cell wall
• Resistance
– Beta-lactamases
– Alteration of PBPs
Beta-Lactams
Cephalosporins
• 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
Beta-Lactams
Cephalosporins
• 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)
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 14:1 ratio)
– Cephalosporins
– Macrolide, Clindamycin, SMZ/TMP
Cost Comparison
Pharyngitis Treatment Options
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
SSTI
Pathogens 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)
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
Antibiotics
Guidelines for Common Infections
• CABP: macrolide, doxycycline, respiratory
quinolone, or β-lactam+macrolide*
– ≥ 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)**
– < 2 yrs old = 10 days
– < 6 yrs old = 7-10 days
– > 6 yrs old = 5-7 days
**Only recommended if bilateral, severe presentation, or
failure to improve after 48-72 hrs of "watchful waiting"
Antibiotics
Guidelines 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
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 ...
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
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
Antibiotics
Cephalosporins
Adverse 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
Beta-Lactams
Carbapenems, 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
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
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
Aminoglycosides
• Nephrotoxicity
– High trough concentrations (Cmin > 2)
– Cumulative exposure, elderly, other nephrotoxic drugs
• Ototoxicity, neuromuscular blockade (high dose)
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)
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)
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
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
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
Rifaximin (Xifaxan)
• Rifamycin antibiotic indicated for (1)
traveler’s 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
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 (<10%) in
healthy volunteers
– Appears to be higher (2- to 6-fold) in patients