4. Concentration-Dependent vs. Time-
Dependent 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
8. Bacteriostatic vs. Bactericidal
• 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
11. Linezolid Spectrum of Activity
• Clinically important Gram + organisms
– MSSA/MRSA, Coag – Staph, E. faecium and
faecalis, Strep. (bactericidal)
– MTb, MAI
12. 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
13. 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, …
14. 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)
16. 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
17. 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)
18. 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)
19. 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)
20. 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
21. 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 (non-
bacteremic)
22. Tigecycline: Side Effects
• Nausea (35%)
• Vomiting (25%)
• Phlebitis
• Increased LFTs (6%)
• Thrombocytopenia, increased PTT and
INR, eosinophilia
• Headache, somnolence, taste perversion
• Remember: No kids under 8yo
23. Ertapenem (Invanz)
• Beta-Lactam
• Bind to PCN-binding proteins (PBPs)
• Concentration-Dependent Killing
• Bactericidal
• Long half life of 4h permits QD dosing
• Renal adjustment required
24. 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
25. Ertapenem: What to use it for
• Intraabdominal infections
• Pneumonia
• Bacteremia
• Bone and soft tissue infections
• Complicated UTIs
• OB/Gyn infections
26. 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
27. Carbapenem: Side Effects
• Rash, urticaria, cross-reaction with PCNs,
nausea, immediate hypersensitivity
• Less epileptogenic than imipenem
28. 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
• Penetrate into cell membranes and disrupt
• Bactericidal and Concentration-Dependent
• Renal adjustment necessary
• Poor levels in pleura, joint, CSF, biliary tract
29. 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
30. Polymyxins: Side Effects
• Dose-Related Reversible Nephrotoxicity
• Dose-Related Reversible Neurotoxicity
manifest as neuromuscular blockade
31. Telavancin (Vibativ)
• 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
32. Telavancin: Spectrum of Activity
and Uses
• MRSA
• Gram positives (but not VRE)
• Uses
– cSSSI
– Nosocomial Pneumonia (with Gram negative
coverage; non-FDA approved)
33. Telavancin: Side Effects
• 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)
35. Echinocandins
• Caspofungin (Cancidas), Micafungin
(Mycamine), Anidulafungin (Eraxis)
• Inhibit glucan synthesis (in cell wall); like
“PCN of antifungals”
• Pregnancy category C
• No renal adjustment required
36. 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
37. 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
38. Echinocandins: Side Effects
• Not cytochrome P450 metabolized
• NOT nephrotoxic or hepatotoxic
• Relatively few/minor side effects
39. 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.
40. 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
41. 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)
42. 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
