Transcript Newer Antibiotics and How We Should Use Them

Newer Antibiotics and How
We Should Use Them
Mahesh C. Patel, M.D.
Division of Infectious Diseases
February 3, 2010
Antibacterials
Timeline
Concentration-Dependent vs. TimeDependent Killing
• Time-Dependent (or Conc. Independent)
– Eliminate bacteria only when time during
which drug concentration is greater than MIC
• Concentration-Dependent
– Eliminate bacteria when their concentrations
are above the MIC of the organism
– Post-antibiotic effect
MIC vs. MBC
Bacteriostatic vs. Bactericidal
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Bactericidal: Kill bacteria
Bacteriostatic: Reversibly inhibit growth
Continuum
No rigorous studies exist showing
superiority of one type over another
• However, -cidal agents preferred in
endocarditis, meningitis, neutropenic
hosts, sepsis
• Static: MIC<MBC; Cidal: MIC=MBC
-Static vs. -Cidal
• Bacteriostatic
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Tetracyclines
Sulphonamides
Trimethoprim
Chloramphenicol
Macrolides
Linosamides
(clindamycin)
• Bactericidal
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Beta-Lactams
Daptomycin
FQs
Aminoglycosides
Metronidazole
TMP/SMX
Nitrofurantoin
Linezolid (Zyvox)
• Oxazolidinone
• Inhibits Protein
Synthesis
• Bacteriostatic
• 600mg po/iv
• No renal adjustment
• Time-Dependent
Killing
Linezolid Spectrum of Activity
• Clinically important Gram + organisms
– MSSA/MRSA, Coag – Staph, E. faecium and
faecalis, Strep. (bactericidal)
– MTb, MAI
Linezolid: What to use it for
• Complicated skin and soft tissue structure
infections (does not include osteomyelitis)
• Nosocomial Pneumonia (MRSA)
• VRE (including bacteremia)
• DO NOT USE for bacteremias
• **(Osteomyelitis, endocarditis, meningitis,
intraabdominal infections, etc.)—ID
consult
Linezolid: Side Effects
• Relatively well-tolerated with GI symptoms
• Serotonin Syndrome
– Fever, agitation, MS changes, tremors if on
serotonergic agents
– Reversible, nonselective monoamine oxidase inhibitor
• Reversible myelosuppresion
– Thrombocytopenia (47% if >10d or rx)
>>anemia>neutropenia
– Duration of treatment > 2 weeks
• Neuropathy (peripheral, optic, etc.); Lactic
Acidosis, …
Daptomycin
• First in a novel class: cyclic lipopeptides
• Side-lined in 1991 as Phase II trials showd
skeletal muscle toxicity with Q12H dosing
• Binds to cell membranes of Gram + organisms
• Bactericidal
• Concentration-Dependent
• Pregnancy Category B
• 4 to 6 mg/kg iv Q24H (Q48H if CrCl<30 mL/min)
Daptomycin (Cubicin)
Daptomycin: Spectrum of Activity
• Like Glycopeptides, though works on organisms
where vancomycin is not effective
• MSSA/MRSA, E faecalis and faecium, Coag
negative Staph, Strep.
• Resistance emerging: If decreased sens to
vancomycin, greater likelihood of decreased
sens to daptomycin.
• Development of resistance during treatment of
Enterococcal infections
Daptomycin: What to use it for
• Complicated SSTI (4mg/kg)
• S. aureus bacteremia and endocarditis (6mg/kg)
• Osteoarticular infections (but would use higher
dose of 8-10mg/kg and use another agent given
lower bone levels and resistance emergence on
therapy
• Enterococcal infections
• DO NOT USE: Pulmonary infections (inactivated
by surfactant)
Daptomycin: Side Effects
• No increased GI
• Paresthesias, dysesthesias, and peripheral
neuropathies
• No QTc issues
• Muscle toxicity
– Begin 7 days after therapy
– Resolve during therapy or about 3 days after
daptomycin is stopped
– Monitor CK when used with other “muscle toxic”
agents (ie HMG-CoA reductase inhibs)
Tigecycline (Tygacil)
• Tetracycline class
• Inhibit bacterial protein
synthesis (30S)
• Bacteriostatic
• 100mg iv once, then
50mg iv Q12H with no
adjustment needed for
renal issues
• Pregnancy Category D
(bone growth and teeth
staining)
Tigecycline: Spectrum of Activity
• Broad range of pathogens
– NO Pseudomonas, Proteus, Morganella, or
Providencia
– Acinetobacter
– MRSA/MSSA, VRE
– Anaerobes
– Resistance by efflux pumps or ribosomal
changes
Tigecycline: What to use it for
• FDA Approved:
• Skin and soft tissue infections
– Intra-Abdominal infections
– Community-acquired pneumonia
– NOT indicated for blood stream infections
• At NBHN, reserved for patients with
resistant GNRod infections (nonbacteremic)
Tigecycline: Side Effects
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Nausea (35%)
Vomiting (25%)
Phlebitis
Increased LFTs (6%)
Thrombocytopenia, increased PTT and
INR, eosinophilia
• Headache, somnolence, taste perversion
• Remember: No kids under 8yo
Ertapenem (Invanz)
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Beta-Lactam
Bind to PCN-binding proteins (PBPs)
Concentration-Dependent Killing
Bactericidal
Long half life of 4h permits QD dosing
Renal adjustment required
Ertapenem: Spectrum of Activity
• Kinda like ceftriaxone and metronidazole
• Gram + bacteria, Enterobacteriaceae,
MSSA, Anaerobes
• NOT: MRSA, Enterococcus; No
Pseudomonas, Acinetobacter
• Resistance: Alteration in PBPs, Beta
Lactamase production, Efflux pumps,
decreased permeability
Ertapenem: What to use it for
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Intraabdominal infections
Pneumonia
Bacteremia
Bone and soft tissue infections
Complicated UTIs
OB/Gyn infections
Doripenem (Doribax)
• Much greater Enterobacteriaceae activity
including Pseudomonas, Acinetobacter
• Lower MICs for GNRs than imipenem or
meropenem
• Resistance to Imipenem does not mean
resistance to Doripenem or meropenem,
or vice versa
• Less beta-lactamase unstable
Carbapenem: Side Effects
• Rash, urticaria, cross-reaction with PCNs,
nausea, immediate hypersensitivity
• Less epileptogenic than imipenem
Polymyxins
• Very old drugs (1947)
• Fell into disuse by 1980 due to nephrotoxicity;
topical and oral use
• Polymyxin B and Polymyxin E (Colistin)
– Polymyxin B (colistemethate) iv
– Colistin for inhalation therapy
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Penetrate into cell membranes and disrupt
Bactericidal and Concentration-Dependent
Renal adjustment necessary
Poor levels in pleura, joint, CSF, biliary tract
Polymyxins: Spectrum of
Activity
• Broad GNR coverage
• Gram +, Gram – cocci, and most
anaerobes are RESISTANT
• Has been used intrathecally and
intraventricularly
• Colistimethate as efficacious as
piperacillin, imipenem, and ciprofloxacin
for treatment of Pseudomonas
Polymyxins: Side Effects
• Dose-Related Reversible Nephrotoxicity
• Dose-Related Reversible Neurotoxicity
manifest as neuromuscular blockade
Telavancin (Vibativ)
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FDA-approved on Sept 11, 2009
Lipoglycopeptide
Synthetic derivative of vancomycin
Bactericidal
Inhibits cell wall synthesis; bacterial
membrane depolarizer
• Once daily iv (10mg/kg)
• Renal adjustment needed
Telavancin: Spectrum of Activity
and Uses
• MRSA
• Gram positives (but not VRE)
• Uses
– cSSSI
– Nosocomial Pneumonia (with Gram negative
coverage; non-FDA approved)
Telavancin: Side Effects
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Mild taste disturbance (33%)
Nausea (27%) and Vomiting (14%)
Insomnia
Coagulation test interference: PT/INR, PTT,
Factor Xa; BUT NO increased risk of bleeding
• Less common: Headache, Red-man Syndrome,
Nephrotoxicity, Diarrhea, Foamy Urine (13%)
• QTc prolongation in 1.5% (vs. 0.6% in
vancomycin)
Anti-Fungals
Echinocandins
• Caspofungin (Cancidas), Micafungin
(Mycamine), Anidulafungin (Eraxis)
• Inhibit glucan synthesis (in cell wall); like
“PCN of antifungals”
• Pregnancy category C
• No renal adjustment required
Echinocandins: Spectrum of
Activity
• Candida spp of all types (fungicidal)
• Aspergillus spp (fungistatic)
• Anidalufungin likley with fewer drug-drug
interactions
• Micafungin has most data in kids
• Caspofungin was 1st
• Caspofungin vs. Micafungin for invasive
Candidiasis  similar results
Echinocandins: Uses
• Invasive and esophageal candidiasis
– Caspo, Anidal., Mica.
• Prophylaxis in HSCT patients
– Mica.
• Invasive aspergillosis in refractory or
intolerant patients
– Caspo
• Fever and neutropenia
– Caspo
Echinocandins: Side Effects
• Not cytochrome P450 metabolized
• NOT nephrotoxic or hepatotoxic
• Relatively few/minor side effects
Newer Azoles
• Voriconazole (VFend), Posaconazole
(Noxafil)
• Many clinically relevant drug-drug
interactions (P450)
• Voriconazole is available in both iv and po
formulations
• Posaconzole available in suspension
• Both with extensive distribution and
penetration into tissues.
Voriconazole
• Invasive aspergillosis (superior to Ampho
B deoxycholate)
• Invasive fusarium and scedosporum
• Esophageal candidiasis (not licensed)
• NOT FDA approved for fever and
neutropenia and possibly inferior to
liposomal Ampho B
Voriconazole: Side Effects
• Similar to other triazoles, EXCEPT:
• Visual disturbance unique
– 30% reported altered or enhanced light perception for
½ hour 30 mins after dose
– Blurred vision, color vision changes, photophobia
– Rarely results in discontinuation
– Mechanism unknown
• Hallucinations (12 of 72 in one study) within
24hrs
• Photosensitivity, QTc prolongation (rare)
Posaconazole (Noxafil)
• Only available orally and bioavailability affected
by food (fat increases absorption)
• No dose adjustment for renal issues
• “Moderate” number of drug-drug interactions
• Indications:
– Prophylaxis of Invasive fungal infections in high risk
patients
– Oropharyngeal candidiasis
– Molds (Aspergillosis, fusariosis, Coccidi.,
eumycetoma, chromoblastomycosis)
• Side Effects: GI and headache