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43 Cards in this Set

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Vancomycin: po/iv Description
Glycopeptide inhibitor of cell wall synthesis
Directly binds to the D-ala-D-ala end terminus of peptidoglycans
Resistance: change to D-ala-D-lac end terminus.

Bactericidal activity varies from strain to strain
Slower killing than beta-lactams
Vancomycin Spectrum of Activity
Spectrum of Activity:

Gram-positives: streptococci, staphylococci, enterococci

Vancomycin resistance is ~20-40% in enterococci from hospitals
Decreased susceptibility/resistance now emerging in Staphylococci
NOTE: VANCOMYCIN USE ON THE RISE

Anaerobes: Clostridium difficile (antibiotic-associated colitis…a.k.a C-diff colitis)

There's an epidemic due to more virulent strains so there's more Vanco.
Current uses of Vanco
Current Uses:
MRSA infections (SSTIs, pneumonia, bloodstream infections, endocarditis)
Clostridium difficile colitis

Main adverse effects:
Rash
“Red-man syndrome”-related to histamine release during drug administration

Drug is not absorbed when administered orally (used only for colitis)

Only trough concentrations should be monitored:
T
arget troughs: 10-20 mg/L
Daptomycin (Cubicin®): IV

MOA
SOA
Clinical Considerations
Mechanism of action:

Lipopeptide antibiotic that directly disrupts cell membrane / cell wall integrity

Spectrum of activity:
Gram-positive organisms:
Streptococci, Staphylococci, Enterococci
MRSA, VRE, strains with decreased vancomycin activity/resistance
DO NOT use for pneumonia (inferior to standard therapies) !!

May cause myositis/rhabdomyelitis (muscle toxicity)
Monitor creatine phosphokinase levels
Fluoroquinolones (FQs)

Mechanism of action
Disrupt normal bacterial DNA synthesis by inhibiting the functions of DNA gyrase and topoisomerase IV
Fluoroquinolones (FQs)

Properties
Mechanism of resistnace
Rapidly Bactericidal
Concentration-dependent

Mechanism of Resistance:

Mutations in DNA gyrase and topoisomerase IV (altered proteins)

Gram (+) and Gram (-) organisms

Overproduction of multidrug efflux pumps (“Acr” or “Mex” pumps)

Gram (-) organisms
Fluoroquinolones (FQs)

Agents
1st Generation

Ciprofloxacin (Cipro®, Ciloxan®): po/iv/topical

Ofloxacin (Floxin®, Ocuflox®): po/iv/topical

Norfloxacin (Noroxin®): po


2nd Gen...

Gemifloxacin (Factive®): po

Levofloxacin (Levaquin®): po/iv

Moxifloxacin (Avelox®): po/iv
Fluoroquinolones


SOA
Gram negatives: active against nearly all

Cipro, Levo are most active FQs against Pseudomonas

Gram-positives:
Newer agents (gemi-, levo-, moxi-) more active than older agents (cipro, norflox, oflox)
Streptococci, Staphylococci, Enterococci (+/-), Bacillus anthracis
Limited activity vs. MRSA

Anaerobes (esp. newer FQs)

Atypical bacteria (including Legionella spp.)

Mycobacteria (including tuberculosis)
Fluoroquinolones: Current Uses
RTIs, sinusitis (newer agents preferred)
SSTIs (but not if MRSA suspected/document)
UTIs (1st line therapy)
exception: moxifloxacin (minimal urine concentrations)
Pseudomonas infections
Use in combination if systemic infection!!! (resistance risks with monotherapy)
Bacterial gastroenteritis (Salmonella)
Cutaneous/Inhalation Anthrax (1st line for bioterrorism-associated)
Ocular infections / otitis externa (topical)
Are nearly all MRSAs floroquinolones resistant?
Yes
Fluoroquinolones: Clinical Considerations
All FQs need dose reductions in patients with moderate-severe renal dysfunction except moxifloxacin (hepatic elimination)

Adverse effects:
May cause photosensitivity / rash
Gemifloxacin: rash more common in younger females (up to 25%)
Musculoskeletal: tendon rupture
Hypo- and/or hyperglycemia:
Especially if concurrent oral hypoglycemic agents
More common with gatifloxacin in elderly patients

Generally avoid in pregnancy / pediatrics (though quinolones are used in CF patients)

Chelated by divalent cations – careful when using P.O. !!!!
Rifampin

MOA
MOR
SOA
Mechanism of action:
Inhibition of bacterial RNA polymerase
Usually bactericidal

Mechanism of resistance:
Altered RNA polymerase enzyme

Spectrum of Activity
Gram-positives: Staphylococci, Streptococci
Gram-negatives: Neisseria meningitidis, Haemophilus
Some atypical antibacterial activity
Mycobacterium tuberculosis, other mycobacteria
Rifampin - Current Uses
First line agent for tuberculosis treatment

Synergistic/additive antibacterial activity in combination with other drugs against gram-positive organisms to treat:

endocarditis, osteomyelitis, meningitis, infections related to prosthetic materials (e.g., hip infection, heart valves)
Potent against biofilm, slow growing bacteria

Prevention of meningitis due to streptococci and/or Haemophilus for contacts of a meningitis patient
Rifampin: Clinical Considerations
Should never be used alone to treat any infection

rapid development of resistance!

Drug turns all bodily fluids red-orange tint

Potent inducer of all CYP450 isoenzymes…many drug interactions!!!
Metronidazole: po/iv/topical

MOA
SOA
Mechanism of Activity:
reduced by low-redox-potential electron transport proteins; directly disrupts DNA and inhibits nucleic acid synthesis

Bactericidal, amoebicidal, and trichomonicidal
concentration-dependent

Spectrum of Activity
Nearly all clinically significant anaerobic bacteria (e.g., Bacteriodes, Clostridium)
Amoebic microorganisms
Trichomonas vaginalis
Helicobacter pylori
Macrolides

MOA
MOR
Mechanism of Activity:

Protein synthesis inhibition via binding to 23S ribosomal RNA at the peptidyl transferase cavity of the 50s ribosomal subunit

Primary Mechanism of Resistance
:
Alteration of macrolide ribosome binding sites via methylations
Examples of Macrolides
Give three


Hint: Begins with C and A and E
Clarithromycin

Azithromycin

Erythromycin
Azithromycin structural properties
- N-methyl group is inserted between
carbons 9 and 10 of erythromycin
more stable to acid degradation
longer half life attributed to
greater and longer tissue penetration
Clarithromycin structural properties
-Methyl ether gives better absorption;
more stable for oral administration with [relatively] less gastric
upset.
-Greater lipophilicity so less frequent dosage required
Antibacterial Activity of Macrolides

Cidal or Static?
Bacteriostatic

Spectrum of activity:
Gram positives:
Streptococci, Staphylococci, Enterococci (+/-)
Gram negatives:
Primarily typical respiratory pathogens (Haemophilus, Moraxella spp.)
Anaerobes: primarily oral anaerobes
Atypical bacteria
Proprionobacteria (acne vulgaris)
Helicobacter pylori
Mycobacteria
Macrolides: Current Clinical Uses
RTIs, sinusitis (esp. azithromycin, clarithromycin)

SSTIs (if PCN/Ceph allergic)

Acne vulgaris (PO and/or topical tx)

Treatment of H. pylori infection (ulcers)

Treatment/prevention of Mycobacterial infections in HIV-Infected patients (azithromycin, clarithromycin)

STDs: Chlymydia, Syphilis treatment (in PCN-allergic patient)
What is the most common side effect of Macrolides?
GI Upset is most common adverse effect!!!
2nd Gen Macrolides
Used for Com Acquired Pneunmo
Linezolid (Zyvox)

MOA
Binds to A site and prevents tRNA from coming in
Linezolid (Zyvox)
MOA
Mechanism of Action:

Oxazolidinone Ribosomal protein synthesis inhibitor (different mechanism/binding site than macrolides, tetracyclines, aminoglycosides)

Inhibits initiation of protein synthesis by selectively binding to 23S ribosomal RNA of the 50S subunit
Prevention of tRNA binding to “A” site
Linezolid (Zyvox)
Clinical Considerations
Reversible MAO Inhibitor:
May cause hypertension if given with tyramine-containing foods, decongestants, …
Fatal/Life-threatening serotonin syndrome has occurred rarely w/ concomitant antidepressant therapy

100% bioavailable (po/iv interchangeable)

Adverse effects: well-tolerated, but:
anemia, thrombocytopenia, rarely neuropathies with longer (>2 week) tx courses
Linezolid (Zyvox®): po/iv

SOA
Gram-positives:
Streptococci
Staphylococci (including MRSA and S. aureus strains with reduced vancomycin susceptibility)
Enterococci (including strains with vancomycin resistance (VRE))

Gram negatives: primarily respiratory pathogens

Bacteriostatic against Staphylococci, Enterococci
Bactericidal versus Streptococci
Clindamycin: po/iv/topical
MOA

SOA

MLS B Class Antibotic
Macrolid
Lincosamides = Clindamycin
Strepogramins
Mechanism of action:
Inhibition of protein synthesis by binding to the 50S subunit of the bacterial ribosome [“MLSB” class]

Spectrum of Activity
Gram-positives: Streptococci, Staphylococci (including some MRSA), Enterococci (+/-)
Most anaerobes (oral anaerobes, Bacteroides)
Minimal activity against Gram-negatives and atypicals.
Usually bacteriostatic
Quinupristin/Dalfopristin (Synercid®)):
Streptogramin antibiotic
[macrolide/lincosamide/streptogramin (“MLSB”) family]

Mechanism of Action:
Both drugs synergistically inhibit bacterial protein synthesis

They do not have activity when they are by themselves
Quinupristin/Dalfopristin (Synercid®

SOA
Bacteriostatic / Bacteriocidal:
resistance to macrolides and clindamycin usually predicts bacteriostatic activity

Spectrum of Activity
Gram-positives:
Streptococci
Staphylococci (including MRSA and strains with reduced vancomycin susceptibility)
Enterococci (including vancomycin-resistant strains)

NO ACTIVITY against Enterococcus faecalis !!! Does have activity againt E. Faecium – Good since 90% that live in gut are Faecium species

Gram-negatives: limited to respiratory pathogens

Some activity against anaerobes and atypical bacteria
Tetracyclines

MOA
MOR
Mechanism of Action:
Protein synthesis inhibition via binding to the 30s ribosomal subunit
Prevents binding of aminoacyl tRNA to the mRNA-ribosomal complex.

Mechanisms of resistance:
Production of efflux proteins (tetA)
Production of ribosomal protection proteins (tetM)
Available Agents

Tetracycline: po

Doxycycline: po/iv

Minocycline: po
Tetracyclines
Bacteriostatic
Spectrum of activity:

Gram positive:
Streptococci, Staphylococci (including some MRSA), enterococci (+/-), Bacillus anthracis
Gram negative: common respiratory pathogens
Oral anaerobes, Proprionobacteria (acne vulgaris), atypical bacteria
Helicobacter pylori
Borrelia burgdorferi, Rickettsia (tick-borne bacteria)
A Glycylcycline drug...

Uses: Intra-abdominal infections, SSTIs
Tigecycline (Tygacil)

IV only
“Broad spectrum” tetracycline
Gram (+), gram (-), anaerobes, tetracycline-resistant orgs.
Uses: Intra-abdominal infections, SSTIs
Clinical Considerations:
Similar to other tetracyclines, but also:
High frequency of nausea/vomiting (~20%)
Aminoglycosides (Drug class)
Mechanism of Action:
Bind to the 30s ribsomal subunit; inhibit initiation of protein synthesis and also causes misreading of the genetic code (i.e. mutant proteins)
Glycosidacally linked amino sugar molecules; contain at least one aminohexose and a highly substituted 1,3-diaminocyclohexane
Most commonly used: amikacin, gentamicin, streptomycin, tobramycin
Theset he ONLY CIDAL drugs
of the protein synthesis inhibition class
Aminoglycosides

MOR
Primary: Enzymatic deactivation by acetylation, phosphorylation, or adenylation of key amino and/or hydroxyl groups
Occurs easily when drug is byitself - similar to the mechanism for Rifamycin
Aminoglycosides

SOA
Rapidly Bactericidal
Concentration-dependent

Spectrum of Activity:

Gram negatives: active against nearly all (including Pseudomonas)

Gram-positives: less active, but synergistic when combined with beta-lactams against streptococci, staphylcocci, enterococci

Mycobacterium tuberculosis (streptomycin)

NO anaerobic/atypical antibacterial activity
Aminoglycosides: Clinical Uses
Goal prevent resistance

In combination with beta-lactams and other antibiotics against streptococci, staphyolcocci, enterococci:

In combination with other gram-negative antibiotics for infections due to hospital-acquired pathogens

Tuberculosis (streptomycin): 2nd/3rd line agent used in multi-drug resistant TB infections

Inhaled (TOBI®): lung infections in cystic fibrosis patients

Topical: ocular infections, otitis externa
Aminoglycosides: Clinical Uses 2
Monotherapy with aminoglycosides results in rapid emergence of resistance
Monitor peak & trough concentrations:
Monitor peak since the conc goes up with dose rate
Peak 10x than MIC is ideal
Peaks (6-10 mg/L with usual doses)
correlate with efficacy
Troughs (< 2 mg/L with usual doses):
correlate with nephrotoxicity
Chloramphenicol

(brought up for historic purposes)
Now there are safer drugs
Used to be good for menigitis. (Penetrates the CNS well)

Protein synthesis inhibition via binding to the 50s ribosomal subunit
First therapeutically important antibiotic to be produced by a totally synthetic route
Excellent CNS penetration
historical drug of choice for meningitis & other CNS infections

SE: Slowly developing anemia. Aplastic anemia (1:200,000)

Need to monitor serum concentrations.
Folate Synthesis Inhibitors
Sulfonamides / Trimethoprim:

1. S inhibits Dihydropteroate synthetase


2. T inhibits Dihydrofolate Reductase
Folate Synthesis Inhibitors

SOA
Spectrum of Activity:

Gram-positives: Streptococci (+/-), Staphylococci (including some MRSA), but NOT enterococci

Gram-negatives: limited to respiratory pathogens and select other organisms (e.g., E. coli, Enterobacter, Proteus)

Pneumocystis jirovici (“PCP”)

Poor against anaerobes and atypical bacteria
Sulfonamides: Current Clinical Uses
Outpatient treatment of S. aureus infections
Including MRSA, w/ confirmed susceptibility

P. jirovici pneumonia treatment/prophylaxis in HIV-infected patients

RTIs, sinusitis, UTIs:
emergence of resistance currently limits use in these settings
Should not be used for pharyngitis (less effective than PCNs/Cephs)
Sulfonamides: Clinical Considerations
Cross-allergenicity exists amongst various sulfas
Trimethoprim may be used for UTI treatment/prevention

Photosensitivity

Hyperkalemia
especially with IV doses, in patients with renal dysfunction, and/or with potassium supplementation

Bone marrow suppression

Drug Interactions:

Protein binding competition/inhibition of metabolism:
Warfarin, glyburide